Pyrimidine compound and medical use  thereof

ABSTRACT

The present invention relates to a pyrimidine compound or a pharmaceutically acceptable salt thereof represented by the following formula [I] 
     
       
         
         
             
             
         
       
     
     wherein each symbol is as defined in the specification and a method of therapeutically or prophylactically treating an undesirable cell proliferation, comprising administering such a compound. The compound of the present invention has superior activity in suppressing undesirable cell proliferation, particularly, an antitumor activity, and is useful as an antitumor agent for the prophylaxis or treatment of cancer, rheumatism, and the like. In addition, the compound of the present invention can be a more effective antitumor agent when used in combination with other antitumor agents such as an alkylating agent or metabolism antagonist.

TECHNICAL FIELD

The present invention relates to a novel pyrimidine compound or apharmaceutically acceptable salt thereof useful as an agent for theprophylaxis or treatment of diseases caused by undesirable cellproliferation, particularly, an antitumor agent. Moreover, the presentinvention relates to novel use of a certain kind of pyrimidine compoundor a pharmaceutically acceptable salt thereof as an agent for theprophylaxis or treatment of a disease caused by undesirable cellproliferation, particularly, as an antitumor agent. More particularly,the present invention relates to a pharmaceutical agent comprising apyrimidine compound showing a p15 protein inducing action and/or a p27protein inducing action and/or an MEK inhibitory action, or apharmaceutically acceptable salt thereof.

BACKGROUND ART

A “cell cycle” means a cycle wherein the period for a cell to divide andonce again divide is one cycle, and this cycle is also referred to as a“cell division cycle”.

A cell cycle includes four phases in a determined order. They are DNAduplication preparation phase (G1 phase), DNA duplication phase (Sphase), division preparation phase (G2 phase) and division phase (Mphase), and regulated by many factors. Among them, the kinase activityof a cyclin/cyclin dependent kinase (CDK) complex is essential for theregulation of the cell cycle.

As a protein to inhibit the kinase activity, a CDK inhibitory protein isknown. The CDK inhibitory proteins of mammalian cells are p21 family andp16 family, both of which are considered to negatively regulate theprogress of cell cycle and responsible for cell differentiation,apoptosis and repair of DNA damage due to irradiation of X ray and thelike. At present, p21, p27 and p57 have been reported as a p21 family,and p16, p15, p18 and p19 have been reported as a p16 family.

When these CDK inhibitory proteins are highly expressed in the cell, thecell proliferation is arrested at G1 phase.

The p21 family shows an inhibitory activity on a relatively wide rangeand plural cyclin/CDK complexes. For example, cyclin E/CDK 2 which is animportant cyclin/CDK complex from G1 phase to G1/S transition phase,cyclin B/Cdc2 which is important for M phase and the like can bementioned. The p16 family is a specific inhibitory factor against cyclinD/CDK 4 and cyclin D/CDK 6, which are one of the cyclin/CDKs in the G1phase, and is considered to dissociate the cyclin/CDK complex by bindingwith CDK 4 and CDK 6, respectively.

From the examination of clinical materials of cancer of esophagus,pancreatic cancer, non-small cell lung cancer, skin cancer and the like,highly frequent incidence of genetic abnormality of P16 has beenreported, and high cancer incidence in p16 knock out mice has beendemonstrated, and therefore, clinical application of p16 inducer hasbeen tried.

Under such situation, p15 protein (aka: INK4B, also simply referred toas p15) has been found as a p16 family. In 1994, induction of p15expression by TGF-β stimulation was confirmed in human keratinocyte cell(HaCaT), and p15 was considered to be one of the factors negativelyregulating the cell cycle. It known that induction of G1 phase cellcycle arrest in HaCaT by TGF-β leads to the suppression of cellproliferation (Letters to Nature, Sep. 15, 1994, vol. 371, pp. 257-261).

While the histondeacetylase (HDAC) inhibitor is known to arrest cellcycles at G1 phase or G2 phase in human cancer cell, it has been foundrecently that trichostatin A, which is an HDAC inhibitor, induces p15gene in human colon cancer cell (HCT116p21(−/−)), and the induction ofp15 by trichostatin A is involved in the inhibition of the cellproliferation of the cancer cells (FEBS Letters, 2003, vol. 554, pp.347-350).

In this way, a compound that induces p15 and/or p27 is expected toinhibit the cell proliferation of cancer cells and the like.

In the meantime, Mitogen-activated protein (MAP) Kinase/extracellularsignal-regulated kinase (ERK) kinase (hereinafter to be referred to asMEK) is known to be involved in the regulation of cell proliferation asa kinase that mediates Raf-MEK-ERK signal transduction pathway, and theRaf family (B-Raf, C-Raf etc.) activates the MEK family (MEK-1, MEK-2etc.) and the MEK family activates the ERK family (ERK-1 and ERK-2).

Activation of Raf-MEK-ERK signal transduction pathway in cancer,particularly colorectal cancer, pancreatic cancer, lung cancer, breastcancer and the like, has been frequently observed.

In addition, since the signals produced by signal molecules such asgrowth factor, cytokine and the like converge to the activation ofMEK-ERK, inhibition of these functions is considered to more effectivelysuppress Raf-MEK-ERK signal transduction than the suppression of thefunction of RTK, Ras, Raf and the like in the upstream.

Moreover, it is also known in recent years that a compound having an MEKinhibitory activity extremely effectively induces inhibition of ERK1/2activity and suppression of cell proliferation (The Journal ofBiological Chemistry, vol. 276, No. 4, pp. 2686-2692, 2001), and thecompound is expected to show effects on the disease caused byundesirable cell proliferation, such as tumor and the like. In addition,an MEK inhibitor is expected to inhibit infiltration or metastaticity ofcells via promotion of expression of Matrix metalloproteinase (MMP) andCD44, and angiogenesis via promotion of expression of vascularendothelial growth factor (VEGF).

Furthermore, application to chronic pain (JP 2003-504401: WO 01/005393),application to diseases or symptoms mediated by neutrophile(JP2002-332247: CA-2385412), application to graft rejection (JP2002-532414: WO 00/35435), application to arthritis (JP 2002-532415: WO00/35436), application to asthma (JP 2002-534380: WO 00/40235),application to viral diseases (JP 2002-534381: WO 00/40237), applicationto diseases caused by deformation or injury of cartilage (WO2002/087620:US 2004/138285), application to Peutz-Jeghers syndrome (WO02/006520) areexpected.

However, such pharmaceutical agent has not been marked heretofore.

As an already commercially available antitumor agent, the followingcompound (Gefitinib) and the like are known (Iressa tablet 250 packageinsert).

JP-A-2004-504294 (patent family: WO2002/006213) describe the followingcompound and the like as compounds having an antitumor activity. Inaddition, the MEK inhibitory activity of such compounds is described(JP-A-2004-504294, pp. 123-124, Example 39, Example 241).

Known compounds relatively similar to the pharmaceutical agent of thepresent invention are described below.

In the literatures issued in 1991, the antitumor activity ofpyrido[2,3-d]pyrimidine derivative has been studied and it described,for example, that some of the following compounds and the like have aninhibitory activity in sarcoma, leukemia cells (Khimiiageterotsiklicheskikh soedinenii, 1991, No. 5, pp. 674-680 (Englishtranslation p. 542, lines 4-7; p. 538, compound IIIa)).

In the literatures issued in 1973, novel synthetic methods of thefollowing compound and the like are disclosed and the antitumor activityof pyrido[2,3-d]pyrimidine derivative is described (Chem. Pharm. Bull.,1973, No. 21, vol. 9, pp. 2014-2018 (p. 2015, chart 2, qompound VIII)).

In these literatures, however, the compound of the present invention isnot disclosed, nor is there found a description suggestive thereof.

Furthermore, WO2002/094824 discloses the following compound and the like(WO2002/094824, p. 55, Example 9) as a therapeutic agent having acytokine regulating action for immune, inflammatory or allergic disease.

In the literatures issued in 1996, synthetic methods of the followingcompound and the like are disclosed (Journal fur Praktische Chemie,1996, vol. 338, pp. 151-156 (p. 154, Table 1, compound 8f)).

In the literatures issued in 1986, synthetic methods of the followingcompound and the like as a synthetic intermediate for aminopterin analoghaving an antitumor activity are disclosed (Journal of MedicinalChemistry, 1986, vol. 29, No. 5, pp. 709-715 (p. 709 abstract; p. 712,Table 1, compound 9b)).

However, this literature does not contain a description relating to theuse of these compounds as antitumor agents, the compound of the presentinvention is not disclosed and a description suggestive thereof is notfound.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a pharmaceutical agentcontaining a pyrimidine compound showing undesirable cell proliferationinhibitory action, particularly an antitumor action or apharmaceutically acceptable salt thereof.

The present inventors have conducted intensive studies in an attempt tofind a compound having such action and completed the present invention.

More particularly, the present invention provides the following (1) to(37).

(1) Use of a compound represented by the following formula [I] or apharmaceutically acceptable salt thereof as an active ingredient for theproduction of a pharmaceutical agent for treating a tumor:

whereinX¹ and X² are the same or different and each is a carbon atom or anitrogen atom, a

moiety is

R¹, R², and R⁶ are the same or different and each isa C₁₋₆ alkyl group,a C₂₋₆ alkenyl group,

-   -   wherein the C₁₋₆ alkyl group and the C₂₋₆ alkenyl group are        optionally substituted by 1 to 3 substituents selected from the        following group A, or

-   -   wherein m is 0 or an integer of 1 to 4,    -   ring Cy is a C₃₋₁₂ carbon ring group or a heterocyclic group,        -   wherein the heterocyclic group is a saturated or unsaturated            ring group having, besides carbon atom, 1 to 4 hetero atoms            selected from an oxygen atom, a nitrogen atom and a sulfur            atom, the C₃₋₁₂ carbon ring group and the heterocyclic group            are optionally substituted by 1 to 5 substituents selected            from the following group B,            R³, R⁴, and R⁵ are the same or different and each is            a hydrogen atom,            a hydroxyl group,            a C₁₋₆ alkyl group,            a C₂₋₆ alkenyl group,    -   wherein the C₁₋₆ alkyl group and the C₂₋₆ alkenyl group are        optionally substituted by 1 to 3 substituents selected from the        following group A,        a C₃₋₁₂ carbon ring group or        a heterocyclic group,    -   wherein the heterocyclic group is a saturated or unsaturated        ring group having, besides carbon atom, 1 to 4 hetero atoms        selected from an oxygen atom, a nitrogen atom and a sulfur atom,        and the C₃₋₁₂ carbon ring group and the heterocyclic group are        optionally substituted by 1 to 5 substituents selected from the        following group B, or        R² and R³ are optionally linked to form a C₁₋₄ alkylene group,        or        R⁴ and R⁵ are optionally linked to form a C₁₋₄ alkylene group,        wherein group A is a group consisting of        1) a halogen atom,        2) a nitro group,        3) a cyano group,        4) a C₁₋₄ alkyl group,        5) —OR^(A1) wherein R^(A1) is a hydrogen atom or a C₁₋₄ alkyl        group,        6) —SR^(A2) wherein R^(A2) is a hydrogen atom or a C₁₋₄ alkyl        group,        7) —NR^(A3)R^(A4) wherein R^(A3) and R^(A4) are the same or        different and each is a hydrogen atom or a C₁₋₄ alkyl group,        8) —COOR^(A5) wherein R^(A5) is a hydrogen atom or a C₁₋₄ alkyl        group,        9) —NR^(A6)COR^(A7) wherein R^(A6) is a hydrogen atom or a C₁₋₄        alkyl group, R^(A7) is a C₁₋₄ alkyl group, a C₃₋₁₂ carbon ring        group or a heterocyclic group,        10) —NR^(A8)COOR^(A9) wherein R^(A8) and R^(A9) are the same or        different and each is a hydrogen atom or a C₁₋₄ alkyl group,        11) a C₃₋₁₂ carbon ring group and        12) a heterocyclic group,    -   wherein the heterocyclic group is a saturated or unsaturated        ring group having, besides carbon atom, 1 to 4 hetero atoms        selected from an oxygen atom, a nitrogen atom and a sulfur atom,    -   each of the C₁₋₄ alkyl groups of the above-mentioned 4), R^(A1),        R^(A2), R^(A3), R^(A4), R^(A5), R^(A6), R^(A7), R^(A8) and        R^(A9) is optionally substituted by the same or different 1 to 3        substituents selected from the following group C, and    -   each of the C₃₋₁₂ carbon ring groups of the above-mentioned 11)        and R^(A7), and the heterocyclic groups of 12) and R^(A7) is        optionally substituted by the same or different 1 to 5        substituents selected from the following group C        group B is a group consisting of        1) a halogen atom,        2) a nitro group,        3) a cyano group,        4) a C₁₋₈a alkyl group,        5) a C₂₋₄ alkenyl group,        6) a C₂₋₄ alkynyl group,        7) —OR^(B1) wherein R^(B1) is a hydrogen atom or a C₁₋₄ alkyl        group,        8) —SR^(B2) wherein R^(B2) is a hydrogen atom or a C₁₋₄ alkyl        group,        9) —NR^(B3)R^(B4) wherein R^(B3) is a hydrogen atom, a C₁₋₄        alkyl group, a C₃₋₁₂ carbon ring group or a heterocyclic group,        and R^(B4) is a hydrogen atom or a C₁₋₄ alkyl group,        10) —NR^(B5)COR^(B6) wherein R^(B5) is a hydrogen atom or a C₁₋₄        alkyl group, and R^(B6) is a hydrogen atom, a C₁₋₄ alkyl group,        a C₃₋₁₂ carbon ring group or a heterocyclic group,        11) —NR^(B7)COOR^(B8) wherein R^(B7) and R^(B8) are the same or        different and each is a hydrogen atom or a C₁₋₄ alkyl group,        12) —NR^(B9)CONR^(B10)R^(B11) wherein R^(B9), R^(B10) and        R^(B11) are the same or different and each is a hydrogen atom or        a C₁₋₄ alkyl group,        13) —NR^(B12)CONR^(B13) OR^(B14) wherein R^(B12), R^(B13) and        R^(B14) are the same or different and each is a hydrogen atom or        a C₁₋₄ alkyl group,        14) —NR^(B15)SO₂R^(B16) wherein R^(B15) is a hydrogen atom or a        C₁₋₄ alkyl group, and R^(B16) is a C₁₋₄ alkyl group, a C₃₋₁₂        carbon ring group or a heterocyclic group,        15) —SO₂—R^(B17) wherein R^(B17) is a C₁₋₄ alkyl group or a        heterocyclic group,        16) —SO₂NR^(B18)R^(B19) wherein R^(B18) and R^(B19) are the same        or different and each is a hydrogen atom or a C₁₋₄ alkyl group,        17) —P(═O)(R^(B20)) (R^(B21)) wherein R^(B20) and R^(B21) are        the same or different and each is a C₁₋₄ alkyl group,        18) —COOR^(B22) wherein R^(B22) is a hydrogen atom or a C₁₋₄        alkyl group,        19) —CONR^(B23)R^(B24) wherein R^(B23) and R^(B24) are the same        or different and each is a hydrogen atom or a C₁₋₄ alkyl group,        20) —NR^(B25)SO₂NR^(B26)R^(B27) wherein R^(B25), R^(B26) and        R^(B27) are the same or different and each is a hydrogen atom or        a C₁₋₄ alkyl group,        21) —NR^(B28)SO₂NR^(B29)CONR^(B30)R^(B31) wherein R^(B28),        R^(B29), R^(B30) and R^(B31) are the same or different and each        is a hydrogen atom or a C₁₋₄ alkyl group,        22) a C₃₋₁₂ carbon ring group and        23) a heterocyclic group    -   wherein each of the “C₁₋₈ alkyl group” of the above-mentioned        4), and the C₁₋₄ alkyl groups for R^(B1) to R^(B31) is        optionally substituted by the same or different 1 to 3        substituents selected from the above-mentioned group A,    -   each of the C₂₋₄ alkenyl group of 5) and the C₂₋₄ alkynyl group        of 6) is optionally substituted by the same or different 1 to 3        substituents selected from the above-mentioned group A,    -   the heterocyclic group is a saturated or unsaturated ring group        having, besides carbon atom, 1 to 4 hetero atoms selected from        an oxygen atom, a nitrogen atom and a sulfur atom, and    -   each of the C₃₋₁₂ carbon ring group of the above-mentioned 22),        R^(B3), R^(B6) and R^(B16), and the heterocyclic group of the        above-mentioned 23), R^(B3), R^(B6), R^(B16) and R^(B17) is        optionally substituted by the same or different 1 to 5        substituents selected from the following group C, and        group C is a group consisting of        1) a halogen atom,        2) a cyano group,        3) a C₁₋₄ alkyl group,        4) —OR^(C1) wherein R^(C1) is a hydrogen atom or a C₁₋₄ alkyl        group,        5) —NR^(C2)R^(C3) wherein R^(C2) and R^(C3) are the same or        different and each is a hydrogen atom or a C₁₋₄ alkyl group,        6) —COOR^(C4) wherein R^(C4) is a hydrogen atom or a C₁₋₄ alkyl        group and        7) an oxo group.        (2) A compound represented by the following formula [I′] or a        pharmaceutically acceptable salt thereof:

whereinR^(1′), R^(2′) and R⁶ are the same or different and each isa C₁₋₆ alkyl group,a C₂₋₆ alkenyl group,

-   -   wherein the C₁₋₆ alkyl group and the C₂₋₆ alkenyl group are        optionally substituted by 1 to 3 substituents selected from        group A of the above-mentioned (1), or

-   -   m is an integer of 0 or 1 to 4,    -   ring Cy is a C₃₋₁₂ carbon ring group or a heterocyclic group        -   wherein the heterocyclic group is a saturated or unsaturated            ring having, besides carbon atom, 1 to 4 hetero atoms            selected from an oxygen atom, a nitrogen atom and a sulfur            atom, and the C₃₋₁₂ carbon ring group and the heterocyclic            group are optionally substituted by 1 to 5 substituents            selected from group B of the above-mentioned (I),            provided that, when the

moiety is

then R^(2′) is not a methyl group, andwhen R^(2′) is a phenyl group, then R^(1′) is not a phenyl group, andother symbols are as defined in the above-mentioned (1).(3) Use of the above-mentioned (1), wherein the compound is representedby the following formula [I-1]:

wherein each symbol in the formula is as defined in the above-mentioned(1).(4) Use of the above-mentioned (1), wherein the compound is representedby the following formula [I-2]:

wherein each symbol in the formula is as defined in the above-mentioned(1).(5) Use of the above-mentioned (1), wherein the compound is representedby the following formula [I-3]:

wherein each symbol in the formula is as defined in the above-mentioned(1).(6) Use of the above-mentioned (1), wherein R¹ is a C₁₋₆ alkyl group.(7) Use of the above-mentioned (1), wherein R¹ is

wherein m is 0, and ring Cy is a C₃₋₁₂ carbon ring group

-   -   wherein the C₃₋₁₂ carbon ring group is optionally substituted by        1 to 5 substituents selected from group B of the above-mentioned        (1).        (8) Use of the above-mentioned (I), wherein R¹ is a C₃₋₈        cycloalkyl group.        (9) Use of the above-mentioned (8), wherein R¹ is a cyclopropyl        group.        (10) Use of the above-mentioned (1), wherein R² is

wherein m is 0, and ring Cy is a C₃₋₁₂ carbon ring group or aheterocyclic groupwherein the C₃₋₁₂ carbon ring group and the heterocyclic group areoptionally substituted by 1 to 5 substituents selected from group B ofthe above-mentioned (1).(11) Use of the above-mentioned (1), wherein R³ is a C₁₋₆ alkyl group.(12) Use of the above-mentioned (1), wherein R⁴ is a hydrogen atom.(13) Use of the above-mentioned (1), wherein R⁵ is a hydrogen atom.(14) Use of the above-mentioned (1), wherein R⁶ is

wherein m is 0, and ring Cy is a C₃₋₁₂ carbon ring group or aheterocyclic group

-   -   wherein the C₃₋₁₂ carbon ring group and the heterocyclic group        are optionally substituted by 1 to 5 substituents selected from        group B of the above-mentioned (1).        (15) Use of a compound of the formula [I] of the        above-mentioned (1) or a pharmaceutically acceptable salt        thereof as an active ingredient for the production of an        antitumor agent.        (16) Use of a compound of the formula [I] of the        above-mentioned (1) or a pharmaceutically acceptable salt        thereof as an active ingredient for the production of a        pharmaceutical agent capable of inhibiting MEK.        (17) Use of a compound of the formula [I] of the        above-mentioned (1) or a pharmaceutically acceptable salt        thereof as an active ingredient for the production of a        pharmaceutical agent capable of inducing p15 protein.        (18) Use of a compound of the formula [I] of the        above-mentioned (1) or a pharmaceutically acceptable salt        thereof as an active ingredient for the production of a        pharmaceutical agents for treating a disease caused by an        undesirable cell proliferation.        (19) Use of the above-mentioned (18), wherein the disease        causing by an undesirable cell proliferation is rheumatism.        (20) Use of a compound of the formula [I] of the        above-mentioned (1) or a pharmaceutically acceptable salt        thereof as an active ingredient for the production of a        pharmaceutical agent capable of inhibiting undesirable cell        proliferation.        (21) Use of a compound of the formula [1] of the        above-mentioned (1) or a pharmaceutically acceptable salt        thereof as an active ingredient for the production of a        pharmaceutical agent capable of regulating cell cycle.        (22) A pharmaceutical composition which comprises a compound of        the formula [I′] of the above-mentioned (2) or a        pharmaceutically acceptable salt thereof, and a pharmaceutically        acceptable carrier.        (23) A pharmaceutical composition for the treatment of a tumor,        which comprises a compound of the formula [I] of the        above-mentioned (1) or a pharmaceutically acceptable salt        thereof, and a pharmaceutically acceptable carrier.        (24) A pharmaceutical composition for treating a disease causing        by an undesirable cell proliferation, which comprises a compound        of the formula [I] of the above-mentioned (1) or a        pharmaceutically acceptable salt thereof, and a pharmaceutically        acceptable carrier.        (25) A commercial package comprising a pharmaceutical        composition of the above-mentioned (23) and a written matter        associated therewith, the written matter stating that the        pharmaceutical composition can or should be used for treating        tumor.        (26) A commercial package comprising a pharmaceutical        composition of the above-mentioned (24) and a written matter        associated therewith, the written matter stating that the        pharmaceutical composition can or should be used for treating        disease causing by an undesirable cell proliferation.        (27) Use of (a) a compound of the formula [I] of the        above-mentioned (1) or a pharmaceutically acceptable salt        thereof as an active ingredient, which is used in combination        with (b) at least one other antitumor compound, for the        production of an antitumor agent.        (28) Use of (a) compound of the formula [I] of the        above-mentioned (1) or a pharmaceutically acceptable salt        thereof as an active ingredient and (b) at least one other        antitumor compound, in combination, for the production of an        antitumor agent.        (29) A pharmaceutical composition comprising, as an active        ingredient, (a) a compound of the formula [I] of the        above-mentioned (1) or a pharmaceutically acceptable salt        thereof and (b) at least one other antitumor compound, and a        pharmaceutical acceptable carrier, in combination.        (30) A kit for treating a tumor comprising (a) a pharmaceutical        composition comprising, as an active ingredient, a compound of        the formula [I] of the above-mentioned (1) or a pharmaceutically        acceptable salt thereof and (b) a pharmaceutical composition        comprising, as an active ingredient, at least one other        antitumor agent, in combination.        (31) An antitumor agent comprising a compound of the formula [I]        of the above-mentioned (1) or a pharmaceutically acceptable salt        thereof as an active ingredient.        (32) A MEK inhibitor comprising a compound of the formula [I] of        the above-mentioned (1) or a pharmaceutically acceptable salt        thereof as an active ingredient.        (33) A p15 protein inducer comprising a compound of the formula        [I] of the above-mentioned (1) or a pharmaceutically acceptable        salt thereof as an active ingredient.        (34) An antitumor agent comprising, as an active ingredient, (a)        a compound of the formula [I] of the above-mentioned (1) or a        pharmaceutically acceptable salt thereof, which is used in        combination with (b) at least one other antitumor compound.        (35) An antitumor agent comprising, as an active ingredient, (a)        a compound of the formula [I] of the above-mentioned (1) or a        pharmaceutically acceptable salt thereof, and (b) at least one        other antitumor compound, in combination.        (36) The agent of the above-mentioned (34), wherein (a) a        compound of the formula [I] of the above-mentioned (1) or a        pharmaceutically acceptable salt thereof and (b) at least one        other antitumor compound are administered to a mammal        simultaneously or sequentially.        (37) The agent of the above-mentioned (35), wherein (a) a        compound of the formula [I] of the above-mentioned (1) or a        pharmaceutically acceptable salt thereof and (b) at least one        other antitumor compound are administered to a mammal        simultaneously or sequentially.

BEST MODE FOR EMBODYING THE INVENTION

The definitions of each substituent and each moiety used in the presentspecification are as follows.

X¹ and X² are the same or different, and each is a carbon atom or anitrogen atom, a

moiety is

preferably,

and particularly preferably

The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atomor an iodine atom, which is preferably a fluorine atom, a chlorine atomor a bromine atom for 1) of group A and 1) of group C, more preferably afluorine atom for 1) of group A, more preferably a fluorine atom or abromine atom for 1) of group C, and preferably a fluorine atom or aniodine atom for 1) of group B.

The “C₁₋₆ alkyl group” is a straight chain or branched chain alkyl grouphaving 1 to 6 carbon atoms, and specifically, methyl group, ethyl group,propyl group, isopropyl group, 2,2-dimethylpropyl group, butyl group,isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexylgroup and the like can be mentioned.

As R¹, R^(1′), R², R² and R⁶, methyl group, ethyl group, propyl group,isopropyl group, 2,2-dimethylpropyl group, butyl group and isobutylgroup are preferable, methyl group and ethyl group are more preferable,and methyl group is particularly preferable. As R³, R⁴ and R⁵, methylgroup, ethyl group, propyl group and isobutyl group are preferable, andmethyl group is more preferable.

The “C₁₋₄alkyl group” is a straight chain or branched chain alkyl grouphaving 1 to 4 carbon atoms, and specifically, methyl group, ethyl group,propyl group, isopropyl group, butyl group, isobutyl group, sec-butylgroup, tert-butyl group and the like can be mentioned.

As 4) of group A and 3) of group C, methyl group and ethyl group arepreferable and methyl group is more preferable. As R^(A1), R^(A2),R^(A3), R^(A4), R^(A5), R^(A6), R^(A7), R^(A8) and R^(A9), methyl group,ethyl group and butyl group are preferable and methyl group is morepreferable. As R^(B1) to R^(B31), methyl group, ethyl group, propylgroup, isopropyl group and butyl group are preferable and methyl group,ethyl group and propyl group are more preferable. As R^(C1), R^(C2),R^(C3), R^(C4) and R^(C5), methyl group and ethyl group are preferableand methyl group is more preferable.

The “C₁₋₉ alkyl group” is a straight chain or branched chain alkyl grouphaving 1 to 8 carbon atoms, and specifically, methyl group, ethyl group,propyl group, isopropyl group, 1-ethyl-1-propyl group, butyl group,isobutyl group, sec-butyl group, tert-butyl group, 3-methylbutyl group,1-propyl-1-butyl group, pentyl group, isopentyl group, hexyl group,heptyl group, octyl group and the like can be mentioned.

As 2) of group B, methyl group, ethyl group, propyl group, isopentylgroup, 1-ethyl-1-propyl group, 3-methylbutyl group and 1-propyl-1-butylgroup are preferable and methyl group and ethyl group are morepreferable.

The “C₂₋₆ alkenyl group” is a straight chain or branched chain alkenylgroup having 2 to 6 carbon atoms, and specifically, vinyl group,1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group,2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group,1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-ethylvinylgroup, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenylgroup, 1,2-dimethyl-1-propenyl group, 1,2-dimethyl-2-propenyl group,1-ethyl-1-propenyl group, 1-ethyl-2-propenyl group, 1-methyl-1-butenylgroup, 1-methyl-2-butenyl group, 2-methyl-1-butenyl group,1-isopropylvinyl group, 2,4-pentadienyl group, 1-hexenyl group,2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group,2,4-hexadienyl group, 1-methyl-1-pentenyl group and the like can bementioned.

As R¹, R^(1′), R², R^(2′), R³, R⁴, R⁵ and R⁶, vinyl group, 1-propenylgroup and 2-propenyl group are preferable and 2-propenyl group is morepreferable.

The “C₂₋₄ alkenyl group” is a straight chain or branched chain alkenylgroup having 2 to 4 carbon atoms, and specifically, vinyl group,1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group,2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group,1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-ethylvinyl groupand the like can be mentioned.

As 5) of group B, vinyl group and 1-propenyl group are preferable, andvinyl group is more preferable.

The “C₂₋₄ alkynyl group” is a straight chain or branched chain alkynylgroup having 2 to 4 carbon atoms, and specifically, ethynyl group,1-propynyl group, 2-propynyl group, isopropynyl group, 1-butynyl group,2-butynyl group, 3-butynyl group, 1-methyl-1-propynyl group,1-methyl-2-propynyl group, 2-methyl-2-propynyl group, 1-ethylethynylgroup and the like can be mentioned.

As 6) of group B, ethynyl group, 1-propynyl group and 1-butynyl groupare preferable, and ethynyl group is more preferable.

The “C₁₋₄ alkylene group” optionally formed by R² in junction with R³and the “C₁₋₄ alkylene group” optionally formed by R⁴ in junction withR⁵ is a straight chain or branched chain alkylene group having 1 to 4carbon atoms, and specifically, methylene group, ethylene group,trimethylene group, 2-methyltrimethylene group, tetramethylene group andthe like can be mentioned.

The “C₁₋₄ alkylene group” optionally formed by R² in junction with R³ ispreferably methylene group, ethylene group or trimethylene group, morepreferably trimethylene group.

The “C₁₋₄alkylene group” optionally formed by R⁴ in junction with R⁵ ispreferably methylene group, ethylene group or trimethylene group, morepreferably ethylene group.

As m, preferred is 0 or an integer of 1 or 2, more preferably 0.

The “C₃₋₁₂ carbon ring group” is a saturated or unsaturated cyclichydrocarbon group having 3 to 12 carbon atoms, which means a phenylgroup, naphthyl group, C₃₋₈cycloalkyl group, or a fused ring group ofC₃₋₈ cycloalkyl and benzene.

The “C₃₋₈ cycloalkyl group” is a saturated cyclic hydrocarbon grouphaving 3 to 8 carbon atoms, and specifically, cyclopropyl group,cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptylgroup, cyclooctyl group, norbornanyl group and the like can bementioned, and preferably cyclopropyl group, cyclobutyl group,cyclopentyl group or cyclohexyl group.

As the “fused ring group of C₃₋₈cycloalkyl group and benzene”, indanylgroup, 1,2,3,4-tetrahydronaphthyl group (1,2,3,4-tetrahydro-2-naphthylgroup, 5,6,7,8-tetrahydro-2-naphthyl group etc.) and the like can bespecifically mentioned, which is preferably indanyl group,1,2,3,4-tetrahydronaphthyl group and the like, and more preferablyindanyl group.

As R¹, R², R³, R⁴, R⁵ and R⁶, phenyl group, cyclopropyl group,cyclobutyl group, cyclopentyl group and cyclohexyl group are preferable,and phenyl group and cyclopropyl group are more preferable. As R¹,cyclopropyl group is particularly preferable, and as R² and R⁶, phenylgroup is particularly preferable. As 11) of group A, R^(A7), 22) ofgroup B, R^(B3), R^(B6) and R^(B16), phenyl group, cyclopropyl group,cyclobutyl group, cyclopentyl group and cyclohexyl group are preferable,and phenyl group and cyclopropyl group are more preferable.

The “heterocyclic group” is a saturated monocyclic ring or anunsaturated monocyclic ring having 5 or 6 ring-constituting atoms, whichcontains, besides carbon atom, 1 to 4 hetero atoms selected from anoxygen atom, a nitrogen atom and a sulfur atom, as a ring-constitutingatom, a fused ring of the monocycle and a benzene ring or a spiro ringof these monocycles or fused rings and the above-mentioned C₃₋₁₂ carbonring, each of which may have 1 to 4, preferably 1 or 2, oxo groups.

As the “heterocyclic group”, which is a monocycle of a saturated ring,pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group,imidazolidinyl group, 2-oxoimidazolidinyl group, 2,4-dioxoimidazolidinylgroup, pyrazolidinyl group, 1,3-dioxolanyl group, 1,3-oxathiolanylgroup, oxazolidinyl group, 2-oxooxazolidinyl group, thiazolidinyl group,piperidinyl group, piperazinyl group, 2-oxopiperazinyl group,tetrahydropyranyl group, tetrahydrothiopyranyl group, dioxanyl group,morpholinyl group, thiomorpholinyl group, 2-oxopyrrolidinyl group,2-oxopiperidinyl group, 4-oxopiperidinyl group, 2,6-dioxopiperidinylgroup, thiadiazolidinyl group (e.g., 1,1-dioxo-1,2,5-thiadiazolidin-2-ylgroup etc.) and the like can be mentioned. Preferably, pyrrolidinylgroup, piperidinyl group, piperazinyl group and morpholinyl group can bementioned.

As the “heterocyclic group”, which is a monocycle of unsaturated ring,pyrrolyl group (e.g., 2-pyrrolyl group etc.), furyl group, thienylgroup, imidazolyl group (e.g., 4-imidazolyl group etc.),1,2-dihydro-2-oxoimidazolyl group, pyrazolyl group (e.g., 5-pyrazolylgroup etc.), diazolyl group, oxazolyl group, isoxazolyl group, thiazolylgroup, isothiazolyl group, 1,2,4-triazolyl group, 1,2,3-triazolyl group,tetrazolyl group, 1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group,1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, furazanyl group,pyridyl group (e.g., 3-pyridyl group etc.), pyrimidinyl group,3,4-dihydro-4-oxopyrimidinyl group, pyridazinyl group, pyrazinyl group,1,3,5-triazinyl group, imidazolinyl group (e.g., 2-imidazolinyl groupetc.), pyrazolinyl group, oxazolinyl group (2-oxazolinyl group,3-oxazolinyl group, 4-oxazolinyl group), isoxazolinyl group, thiophenylgroup, thiazolinyl group, isothiazolinyl group, pyranyl group,2-oxopyranyl group, 2-oxo-2,5-dihydrofuranyl group,1,1-dioxo-1H-isothiazolyl group and the like can be mentioned.Preferably, pyrrolyl group, thienyl group, imidazolyl group, pyrazolylgroup, oxazolyl group, isooxazolyl group, thiophenyl group, thiazolylgroup, isothiazolyl group and pyridyl group can be mentioned.

As the “heterocyclic group” which is a fused ring of monocycle andbenzene ring, indolyl groups (e.g., 4-indolyl group, 5-indolyl group,6-indolyl group, 7-indolyl group etc.), isoindolyl group,1,3-dihydro-1,3-dioxoisoindolyl group and benzofuranyl groups (e.g.,4-benzofuranyl group, 7-benzofuranyl group etc.), indazolyl group,isobenzofuranyl group and benzothiophenyl groups (e.g.,4-benzothiophenyl group, 5-benzothiophenyl group, 7-benzothiophenylgroup etc.), benzoxazolyl groups (e.g., 4-benzoxazolyl group,7-benzoxazolyl group etc.), benzimidazolyl groups (e.g.,4-benzimidazolyl group, 5-benzimidazolyl group, 7-benzimidazolyl groupetc.), benzothiazolyl groups (e.g., 4-benzothiazolyl group,7-benzothiazolyl group etc.), quinolyl group, isoquinolyl group,1,2-dihydro-2-oxoquinolyl group, quinazolinyl group, quinoxalinyl group,cinnolinyl group, phthalazinyl group, 2,3-dihydroindolyl group,isoindolinyl group, 1,2,3,4-tetrahydroquinolyl group,2-oxo-1,2,3,4-tetrahydroquinolyl group, benzo[1,3]dioxolyl group,chromanyl group, isochromanyl group,

and the like can be mentioned.

As the spiro ring of the above-mentioned monocycle or fused ring and theabove-mentioned C₃₋₁₂ carbon ring, for example, groups represented bythe following formulas can be mentioned.

Preferably, it is a fused ring group of monocyclic 5- or 6-memberedheterocycle and a benzene ring, which is specifically, indolyl group,indazolyl group, benzothiophenyl group, benzimidazolyl group,2,3-dihydroindolyl group, 1,2,3,4-tetrahydroquinolyl group,benzo[1,3]dioxolyl group and the like.

As R¹, R², R³, R⁴, R⁵ and R⁶, pyrrolidinyl group, piperidinyl group,piperazinyl group, morpholinyl group, pyridinyl group, thiophenyl group,thiazolyl group, indolyl group, indazolyl group, benzothiophenyl group,benzimidazolyl group, 2,3-dihydroindolyl group,1,2,3,4-tetrahydroquinolyl group and benzo[1,3]dioxolyl group arepreferable, and piperidinyl group, pyridinyl group, thiophenyl group,thiazolyl group, indolyl group, indazolyl group, benzothiophenyl group,benzimidazolyl group, 2,3-dihydroindolyl group,1,2,3,4-tetrahydroquinolyl group, benzo[1,3]dioxolyl group are morepreferable. As 12) of group A, R^(A7) and 23) of group B, R^(B3),R^(B6), R^(B16) and R^(B17), pyrrolidinyl group, piperidinyl group,piperazinyl group, morpholinyl group, pyridyl group and oxazolinyl groupare preferable, and pyrrolidinyl group, piperidinyl group, piperazinylgroup and morpholinyl group are more preferable.

The “C₁₋₆ alkyl group” and “C₂₋₆ alkenyl group” for R¹, R² and R⁶, andR³, R⁴ and R⁵ are optionally substituted by 1 to 3 substituents selectedfrom group A. That is, the above-defined “C₁₋₆ alkyl group” and “C₂₋₆alkenyl group” may be substituted by 1 to 3 substituents selected fromgroup A, and include unsubstituted “C₁₋₆ alkyl group” and unsubstituted“C₂₋₆ alkenyl group”.

Each of the above-defined “C₁₋₈ alkyl group” for the below-defined 4) ofgroup B, and the above-defined “C₁₋₄ alkyl group” for R^(B1) to R^(B31)is optionally substituted by the same or different 1 to 3 substituentsselected from group A.

Each of the above-defined “C₂₋₄ alkenyl group” for the below-defined 5)of group B and the above-defined “C₂₋₄ alkynyl group” for 6) isoptionally substituted by the same or different 1 to 3 substituentsselected from group A.

The “group A” is a group consisting of 1) the above-defined “halogenatom”, 2) nitro group, 3) cyano group, 4) the above-defined “C₁₋₄ alkylgroup”, 5) “—OR^(A1)”, 6) “—SR^(A2)”, 7) “—NR^(A3)R^(A4)”, 8)“—COOR^(A5)”, 9) “—NR^(A6)COR^(A7)”, 10) “—NR^(A8)COOR^(A9)”, 11) theabove-defined “C₃₋₁₂ carbon ring group” and 12) the above-defined“heterocyclic group”, wherein R^(A1), R^(A2), R^(A3), R^(A4), R^(A5),R^(A6), R^(A8) and R^(A9) are the same or different and each is ahydrogen atom, or, the above-defined “C₁₋₄ alkyl group”, R^(A7) is theabove-defined “C₁₋₄ alkyl group”, the above-defined “C₃₋₁₂ carbon ringgroup” or the above-defined “heterocyclic group”.

As the “—OR^(A1)”, hydroxyl group, methoxy group, ethoxy group, propoxygroup, isopropyloxy group, tert-butoxy group and the like can bespecifically mentioned.

As the “—SR^(A2)”, mercapto group, methylsulfanyl group, ethylsulfanylgroup, propylsulfanyl group, isopropylsulfanyl group, tert-butylsulfanylgroup and the like can be specifically mentioned.

As the “—NR^(A3)R^(A4)”, amino group, methylamino group, ethylaminogroup, propylamino group, isopropylamino group, tert-butylamino group,dimethylamino group, diethylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-isopropyl-N-methylamino group and thelike can be specifically mentioned.

As the “—COOR^(A5)”, carboxyl group, methoxycarbonyl group,ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group,tert-butoxycarbonyl group and the like can be specifically mentioned.

As the “—NR^(A6)COR^(A7)”, acetylamino group, propionylamino group,butyrylamino group, isobutyrylamino group, pivaloylamino group,N-acetyl-N-methylamino group, butylcarbonylamino group and the like canbe specifically mentioned.

As the “—NR^(A8)COOR^(A9)”, carboxyamino group, carboxymethylaminogroup, carboxyethylamino group, methoxycarbonylamino group,methoxycarbonylmethylamino group and the like can be specificallymentioned.

As the “group A”, preferably, fluorine atom, chlorine atom, bromineatom, methyl group, ethyl group, propyl group, hydroxyl group, methoxygroup, ethoxy group, propoxy group, amino group, methylamino group,ethylamino group, dimethylamino group, diethylamino group, carboxyaminogroup, butylcarbonylamino group, carboxy group, phenyl group,4-morpholinyl group, 1-pyrrolidinyl group, 1-piperidinyl group and1-piperazinyl group can be mentioned.

As the “group A”, particularly preferably, fluorine atom, chlorine atom,methyl group, hydroxyl group, methoxy group, amino group, dimethylaminogroup, diethylamino group, carboxyamino group, butylcarbonylamino group,carboxy group, phenyl group, 4-morpholinyl group, 1-pyrrolidinyl group,1-piperidinyl group and 1-piperazinyl group can be mentioned.

The preferable number of the substituent is 1, and the substituent maybe used at any substitutable position.

The “C₃₋₁₂ carbon ring group” and “heterocyclic group” for ring Cy, and“C₃₋₁₂ carbon ring group” and “heterocyclic group” for R³, R⁴ or R⁵ areoptionally substituted by 1 to 5 substituents selected from group B.That is, the above-defined “C₃₋₁₂ carbon ring group” and “heterocyclicgroup” may be substituted by 1 to 5 substituents selected from group B,and includes unsubstituted “C₃₋₁₂ carbon ring group” and unsubstituted“heterocyclic group”.

The “group B” is a group consisting of 1) the above-defined “halogenatom”, 2) a nitro group, 3) a cyano group, 4) the above-defined “C₁₋₈alkyl group”, 5) the above-defined “C₂₋₄ alkenyl group”, 6) theabove-defined “C₂₋₄ alkynyl group”, 7) “—OR^(B1)”, 8) “—SR^(B2)”, 9)“—NR^(B3)R^(B4)”, 10) “—NR^(B5)COR^(B6)”, 11) “—NR^(B7)COOR^(B8)”, 12)“—NR^(B9)CONR^(B10)R^(B11)”, 13) “—NR^(B12)CONR^(B13)OR^(B14)”, 14)“—NR^(B15)SO₂R^(B16)”, 15) “—SO₂—R^(B17)”, 16) “—SO₂NR^(B18)R^(B19)”,17) “—P(═O) (R^(B20)) (R^(B21))”, 18) “—COOR^(B22)”, 19)“—CONR^(B23)R^(B24)”, 20) “—NR^(B25)SO₂NR^(B26)R^(B27)”, 21)“—NR^(B28)SO₂NR^(B29)CONR^(B30)R^(B31)”, 22) the above-defined “C₃₋₁₂carbon ring group” and 23) the above-defined “heterocyclic group”,wherein R^(B1), R^(B2), R^(B4), R^(B5), R^(B7), R^(B8), R^(B9), R^(B10),R^(B11), R^(B12), R^(B13), R^(B14), R^(B15), R^(B18), R^(B19), R^(B22),R^(B23), R^(B24), R^(B25), R^(B26), R^(B27), R^(B28), R^(B29), R^(B30)and R^(B31) are the same or different and each is a hydrogen atom or theabove-defined “C₁₋₄ alkyl group”, R^(B3) and R^(B6) are each a hydrogenatom, the above-defined “C₁₋₄ alkyl group”, the above-defined “C₃₋₁₂carbon ring group” or the above-defined “heterocyclic group”, R^(B16) isthe above-defined “C₁₋₄ alkyl group”, the above-defined “C₃₋₁₂ carbonring group” or the above-defined “heterocyclic group”, R^(B17) is theabove-defined “C₁₋₄ alkyl group” or the above-defined “heterocyclicgroup”, and R^(B20) and R^(B21) are the same or different and each isthe above-defined “C₁₋₄ alkyl group”.

As the “—OR^(B1)”, hydroxyl group, methoxy group, ethoxy group, propoxygroup, isopropyloxy group, tert-butoxy group and the like can bespecifically mentioned.

As the “—SR^(B2)”, mercapto group, methylsulfanyl group, ethylsulfanylgroup, propylsulfanyl group, isopropylsulfanyl group, tert-butylsulfanylgroup and the like can be specifically mentioned.

As the “—NR^(B3)R^(B4)”, amino group, methylamino group, ethylaminogroup, 2-aminoethylamino group, propylamino group, isopropylamino group,tert-butylamino group, dimethylamino group, diethylamino group,N-ethyl-N-methylamino group, N-methyl-N-propylamino group,N-isopropyl-N-methylamino group, N-(imidazolin-2-yl)amino group and thelike can be specifically mentioned.

As the “—NR^(B5)COR^(B6)”, amino group, formylamino group, acetylaminogroup, hydroxyacetylamino group, propionylamino group, butyrylaminogroup, isobutyrylamino group, pivaloylamino group,N-acetyl-N-methylamino group, 3-aminopropionylamino group,3-(pentanoylamino)propionylamino group, 4-imidazolylcarbonylamino group,(l-methylpyrrol-2-yl)carbonylamino group, 4-pyrazolylcarbonylamino groupand the like can be specifically mentioned.

As the “—NR^(B7)COOR^(B8)”, carboxyamino group, carboxymethylaminogroup, carboxyethylamino group, methoxycarbonylamino group,methoxycarbonylmethylamino group and the like can be specificallymentioned.

As the “—NR^(B9)CONR^(B10)R^(B11)”, aminocarbonylamino group,methylaminocarbonylamino group, dimethylaminocarbonylamino group,(methylaminocarbonyl)(methyl)amino group,(dimethylaminocarbonyl)(methyl)amino group,[(2-hydroxyethyl)carbamoyl]amino and the like can be specificallymentioned.

As the “—NR^(B12)CONR^(B13)OR^(B14)”, methoxyaminocarbonylamino group,(methylmethoxyaminocarbonyl)(methyl)amino group,(methylmethoxyaminocarbonyl)amino group and the like can be specificallymentioned.

As the “—NR^(B15)SO₂R^(B16)”, sulfonylamino group, methylsulfonylaminogroup, ethylsulfonylamino group, propylsulfonylamino group,N-methyl-N-sulfonylamino group, N-methyl-N-methylsulfonylamino group,N-ethyl-N-sulfonylamino group, N-ethyl-N-methylsulfonylamino group,3-pyridylsulfonylamino group, morpholinosulfonylamino group,piperidinomorpholinosulfonylamino group, 2-morpholinoethylsulfonylaminogroup and the like can be specifically mentioned.

As the “—SO₂—R^(B17)”, sulfonyl group, methylsulfonyl group,ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group and thelike can be specifically mentioned.

As the “—SO₂NR^(B18)R^(B19), aminosulfonyl group, methylaminosulfonylgroup, dimethylaminosulfonyl group, ethylmethylaminosulfonyl group andthe like can specifically be mentioned.

As the “—P(═O) (R^(B20)) (R^(B21))”, phosphinoyl group,methylphosphinoyl group, dimethylphosphinoyl group, ethylphosphinoylgroup, diethylphosphinoyl group and the like can be specificallymentioned.

As the “—COOR^(B22), carboxyl group, methoxycarbonyl group,ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group,tert-butoxycarbonyl group and the like can be specifically mentioned.

As the “—CONR^(B23)R^(B24), carbamoyl, methylcarbamoyl,dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl,butylcarbamoyl and the like can be specifically mentioned.

As the “—NR^(B25)SO₂NR^(B26)R^(B27), sulfamoylamino group,dimethylsulfamoylamino group and the like can be specifically mentioned.

As the “—NR^(B28)SO₂NR^(B29)CONR^(B30)R³¹”,{[(2-hydroxyethyl)carbamoyl](2-hydroxyethyl)sulfamoyl}amino group andthe like can be specifically mentioned.

As the “group B”, preferably, fluorine atom, chlorine atom, bromineatom, iodine atom, nitro group, cyano group, methyl group, ethyl group,propyl group, isopropyl group, butyl group, isobutyl group, pentylgroup, isopentyl group, hexyl group, 1-ethylpropyl group, 1-propylbutylgroup, vinyl group, 1-propenyl group, ethynyl group, 1-propynyl group,1-butynyl group, hydroxyl group, methoxy group, ethoxy group, propoxygroup, isopropoxy group, methylthio group, ethylthio group, amino group,methylamino group, ethylamino group, dimethylamino group, diethylaminogroup, ethylmethylamino group, methylcarbonylamino group,ethylcarbonylamino group, propylcarbonylamino group,isopropylcarbonylamino group, (methylcarbonyl)(methyl)amino group,ethoxycarbonylamino group, methylaminocarbonylamino group,dimethylaminocarbonylamino group, methoxyaminocarbonylamino group,methylsulfonylamino group, ethylsulfonylamino group, propylsulfonylaminogroup, isopropylsulfonylamino group, phenylsulfonylamino group,(methylsulfonyl)(methyl)amino group, methylsulfonyl group,piperazin-1-ylsulfonyl group, morpholin-4-ylsulfonyl group,piperidin-4-ylsulfonyl group, pyrrolidin-4-ylsulfonyl group,aminosulfonyl group, methylaminosulfonyl group, ethylaminosulfonylgroup, dimethylaminosulfonyl group, dimethylphosphinoyl group, carboxygroup, methoxycarbonyl group, carbamoyl group, methylaminocarbonylgroup, ethylaminocarbonylamino group, dimethylaminosulfonylamino group,cyclopropyl group, cyclohexyl group, phenyl group, piperidinyl group,pyrrolidinyl group, piperidinyl group, piperazinyl group and morpholinylgroup can be mentioned.

As the “group B”, particularly preferably, fluorine atom, chlorine atom,bromine atom, iodine atom, nitro group, cyano group, methyl group, ethylgroup, propyl group, isopropyl group, butyl group, 1-ethylpropyl group,1-propylbutyl group, butyl group, isobutyl group, isopentyl group, vinylgroup, ethynyl group, 1-propynyl group, 1-butynyl group, hydroxyl group,methoxy group, propoxy group, isopropoxy group, methylthio group, aminogroup, methylamino group, ethylamino group, dimethylamino group,diethylamino group, ethylmethylamino group, methylcarbonylamino group,ethylcarbonylamino group, propylcarbonylamino group,isopropylcarbonylamino group, (methylcarbonyl)(methyl)amino group,ethoxycarbonylamino group, methylaminocarbonylamino group,dimethylaminocarbonylamino group, methoxyaminocarbonylamino group,methylsulfonylamino group, ethylsulfonylamino group, propylsulfonylaminogroup, isopropylsulfonylamino group, phenylsulfonylamino group,(methylsulfonyl)(methyl)amino group, methylsulfonyl group,piperazin-1-ylsulfonyl group, morpholin-4-ylsulfonyl group,piperidin-4-ylsulfonyl group, pyrrolidin-4-ylsulfonyl group,aminosulfonyl group, methylaminosulfonyl group, ethylaminosulfonylgroup, dimethylaminosulfonyl group, dimethylphosphinoyl group, carboxygroup, methoxycarbonyl group, carbamoyl group, methylaminocarbonylgroup, ethylaminocarbonylamino group, dimethylaminosulfonylamino group,cyclopropyl group, phenyl group, piperidinyl group, pyrrolidinyl group,piperidinyl group, piperazinyl group and morpholinyl group can bementioned.

The preferable number of substituent is 1 or 2, and when the “C₃₋₁₂carbon ring group” is a phenyl group, ring Cy is preferablymono-substituted at the 2-position, mono-substituted at the 3-position,mono-substituted at the 4-position, di-substituted at the 2,3-position,di-substituted at the 2,4-position, di-substituted at the 2,5-positionor di-substituted at the 2,6-position, and particularly preferablymono-substituted at the 4-position or di-substituted at the2,4-position, R² is more preferably mono-substituted at the 3-position,and R⁶ is more preferably di-substituted at the 2,4-position.

Each of the above-defined “C₁₋₄ alkyl group” for 4) of the above-definedgroup A, and the above-defined “C₁₋₄ alkyl group” for R^(A1), R^(A2),R^(A3), R^(A4), R^(A5), R^(A6), R^(A7), R^(A8) or R^(A9) is optionallysubstituted by the same or different 1 to 3 substituents selected fromthe below-defined “group C”.

Each of the above-defined “C₃₋₁₂ carbon ring group” for 11) of group Aand R^(A7), and the above-defined “heterocyclic group” for 12) andR^(A7) is optionally substituted by the same or different 1 to 5substituents selected from the below-defined “group C”.

Each of the above-defined “C₃₋₁₂ carbon ring group” for theabove-mentioned 22) of group B, R^(B3), R^(B6) and R^(B16), and theabove-defined “heterocyclic group” for the above-mentioned 23), R^(B3),R^(B6), R^(B16) and R^(B17) is optionally substituted by the same ordifferent 1 to 5 substituents selected from the below-defined “group C”.

The “group C” is a group consisting of 1) the above-defined “halogenatom”, 2) a cyano group, 3) the above-defined “C₁₋₄ alkyl group”, 4)“—OR^(C1)”, 5) “—NR^(C2)R^(C3)”, 6) “—COOR^(C4)” and 7) an oxo group,wherein R^(C), R^(C2), R^(C3) and R^(C4) are the same or different andeach is a hydrogen atom or the above-defined “C₁₋₄ alkyl group”.

As the —OR^(C1)”, hydroxyl group, methoxy group, ethoxy group, propoxygroup, isopropoxy group, tert-butoxy group and the like can bespecifically mentioned.

As the “—NR^(C2)R^(C3)”, amino group, methylamino group, ethylaminogroup, propylamino group, isopropylamino group, tert-butylamino group,dimethylamino group, diethylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-isopropyl-N-methylamino group and thelike can be specifically mentioned.

As the “—COOR^(C4)”, carboxyl group, methoxycarbonyl group,ethoxycarbonyl group, propoxycarbonyl group, isopropyloxycarbonyl group,tert-butoxycarbonyl group and the like can be specifically mentioned.

As the “group C”, the group consisting of 1) the above-defined “halogenatom”, 2) a cyano group, 3) the above-defined “C₁₋₄ alkyl group”, 4)“—OR^(C1)”, 5) “—NR^(C2)R^(C3)” and 6) “—COOR^(C4)” are preferable, andspecifically, fluorine atom, chlorine atom, bromine atom, cyano group,methyl group, ethyl group, propyl group, hydroxyl group, methoxy group,ethoxy group, amino group, dimethylamino group, diethylamino group,carboxyl group and methoxycarbonyl group can be mentioned.

As the “group C”, methyl group is particularly preferable.

The preferable number of the substituent is 1, and the substituent maybe used at any substitutable position.

As the “R¹”, preferably, a C₁₋₆ alkyl group (wherein the C₁₋₆ alkylgroup is optionally substituted by 1 to 3 substituents selected fromgroup A) or

wherein each symbol is as defined above, can be mentioned.

Here, m is preferably 0, the “ring Cy” is preferably C₃₋₁₂ carbon ringgroup, and the “carbon ring group” is preferably cycloalkyl group(wherein the “C₃₋₁₂ carbon ring group” and “cycloalkyl group” areoptionally substituted by 1 to 5 substituents selected from group B).

Specifically, as the “R¹”, methyl group, ethyl group,2,2,2-trifluoroethyl group, propyl group, isopropyl group, butyl group,2-propenyl group, cyclopropyl group, 2-methylcyclopropyl group,cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group,4-chlorophenyl group, 4-fluorophenyl group, o-tolyl group, m-tolylgroup, p-tolyl group, 4-methoxyphenyl group, thiophen-3-yl group,cyclopropylmethyl group, 2-methoxyethyl, carboxymethyl, 2-hydroxyethyl,2-(dimethylamino)ethyl and benzyl group are preferable.

More preferably, methyl group, ethyl group, 2,2,2-trifluoroethyl group,propyl group, isopropyl group, butyl group, cyclopropyl group,2-methylcyclopropyl group, cyclobutyl group, cyclopentyl group,cyclohexyl group, phenyl group, 4-chlorophenyl group, 4-fluorophenylgroup, o-tolyl group, m-tolyl group, p-tolyl group, 4-methoxyphenylgroup, thiophen-3-yl group, 2-methoxyethyl, carboxymethyl,2-hydroxyethyl and 2-(dimethylamino)ethyl, particularly preferably,methyl group or cyclopropyl group can be mentioned.

As the “R²”,

wherein each symbol is as defined above, is preferable. Here, m ispreferably 0, the “ring Cy” is preferably C₃₋₁₂ carbon ring group, andthe “carbon ring group” is preferably phenyl group (wherein the “C₃₋₁₂carbon ring group” and “phenyl group” are optionally substituted by 1 to5 substituents selected from group B, and as the “group B”,“—NR^(B3)R^(B4)”, “—NR^(B5)COR^(B6)”, “—NR^(B7)COOR^(B8)”,“—NR^(B9)CONR^(B10)R^(B11)”, “—NR^(B12)CONR^(B13)OR^(B14)”,“—NR^(B15)SO₂R^(B16)” “—NR^(B25)SO₂NR^(B26)R^(B27)”, and“—NR^(B28)SO₂NR^(B29)CONR^(B30)R^(B31)” are preferable).

Specifically, as the “R²”, a hydrogen atom, methyl group, ethyl group,2,2,2-trifluoroethyl group, isopropyl group, butyl group, isobutylgroup, 2-propenyl group, cyclopropyl group, cyclobutyl group,cyclopentyl group, phenyl group, 4-chlorophenyl group, 2-fluorophenylgroup, 4-fluorophenyl group, 4-bromophenyl group, 2,6-difluorophenylgroup, o-tolyl group, m-tolyl group, p-tolyl group, 2,6-dimethylphenylgroup, 2-ethylphenyl group, 3-(3-hydroxypropyl)phenyl group,3-(2-carboxyethyl)phenyl group, 3-(3-morpholin-4-ylpropyl)phenyl group,3-dimethylaminopropylphenyl group, 3-hydroxyphenyl group,4-hydroxyphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group,4-methoxyphenyl group, 3-dimethylaminoethoxyphenyl group,3-carboxymethoxyphenyl group, 3-(3-dimethylaminopropoxy)phenyl group,3-(2-morpholin-4-ylethoxy)phenyl group,3-(2-pyrrolidin-1-ylethoxy)phenyl group,3-(2-piperidin-1-ylethoxy)phenyl group, 3-(2-diethylaminoethoxy)phenylgroup, 3-[3-(4-methylpiperazin-1-yl)propoxy]phenyl group, 3-aminophenylgroup, 3-methylaminophenyl group, 3-dimethylaminophenyl group,3-(methanesulfonyl)methylaminophenyl group, 3-methylcarbonylaminophenylgroup, 3-methanesulfonylaminophenyl group,4-chloro-3-methanesulfonylaminophenyl group, 3-ethanesulfonylaminophenylgroup, 3-(propane-1-sulfonylamino)phenyl group,3-(propane-2-sulfonylamino)phenyl group,3-chloromethanesulfonylaminophenyl group,3-trifluoromethanesulfonylaminophenyl group,3-(2,2,2-trifluoroethanesulfonylamino)phenyl group,3-(2-methoxyethyl)methylaminophenyl group, 3-methylcarbonylaminophenylgroup, 3-ethylcarbonylaminophenyl group, 3-propylcarbonylaminophenylgroup, 3-isopropylcarbonylaminophenyl group, 3-ethoxycarbonylaminophenylgroup, 3-(hydroxymethylcarbonyl)aminophenyl group,3-(2-hydroxyethylcarbonylamino)phenyl group,3-ethylaminocarbonylaminophenyl group,3-(2-dimethylaminoethylcarbonylamino)phenyl group,3-(3-dimethylaminopropylcarbonylamino)phenyl group,3-(methoxymethylcarbonylamino)phenyl group,3-(butylcarbonylaminomethylcarbonylamino)phenyl group,3-(2-butylcarbonylaminoethylcarbonylamino)phenyl group,3-methylaminocarbonylaminophenyl group,3-methoxyaminocarbonylaminophenyl group,3-dimethylaminocarbonylaminophenyl group,3-(dimethylaminomethylcarbonylamino)phenyl group,3-(2-morpholin-4-ylethylamino)phenyl group,3-(2-benzyloxycarbonylaminoethyl)sulfonylaminophenyl group,3-(2-aminoethyl)sulfonylaminophenyl group,3-(2-butylcarbonylaminoethyl)sulfonylaminophenyl group,3-dimethylaminosulfonylaminophenyl group, 3-carboxyphenyl group,3-carbamoylphenyl group, 3-methanesulfonylphenyl group,4-methanesulfonylphenyl group, 3-ethanesulfonylphenyl group,3-methylaminosulfonyiphenyl group, 3-ethylaminosulfonylphenyl group,3-benzenesulfonylaminophenyl group, 3-aminosulfonylphenyl group,3-dimethylaminosulfonylphenyl group, 4-dimethylaminosulfonylphenylgroup, 3-(4-methylpiperazine-1-sulfonyl)phenyl group,3-(morpholine-4-sulfonyl)phenyl group, 3-(piperidine-1-sulfonyl)phenylgroup, 3-(pyrrolidine-1-sulfonyl)phenyl group,3-methylaminocarbonylphenyl group, 3-morpholin-4-ylphenyl group,3-pyrrolidin-1-ylphenyl group, 3-piperidin-1-ylphenyl group,3-(4-methylpiperazin-1-yl)phenyl group, 3-(2-oxopyrrolidin-1-yl)phenylgroup, 3-(3-oxomorpholin-4-yl)phenyl group, thiophen-3-yl group,pyridin-3-yl group, benzyl group and the following groups:

are preferable.

More preferably, phenyl group, 4-chlorophenyl group, 2-fluorophenylgroup, 4-fluorophenyl group, 4-bromophenyl group, 2,6-difluorophenylgroup, o-tolyl group, m-tolyl group, p-tolyl group, 2,6-dimethylphenylgroup, 2-ethylphenyl group, 3-(3-hydroxypropyl)phenyl group,3-(2-carboxyethyl)phenyl group, 3-(3-morpholin-4-ylpropyl)phenyl group,3-dimethylaminopropylphenyl group, 3-hydroxyphenyl group,4-hydroxyphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group,4-methoxyphenyl group, 3-dimethylaminoethoxyphenyl group,3-carboxymethoxyphenyl group, 3-(3-dimethylaminopropoxy)phenyl group,3-(2-morpholin-4-ylethoxy)phenyl group,3-(2-pyrrolidin-1-ylethoxy)phenyl group,3-(2-piperidin-1-ylethoxy)phenyl group, 3-(2-diethylaminoethoxy)phenylgroup, 3-[3-(4-methylpiperazin-1-yl)propoxy]phenyl group, 3-aminophenylgroup, 3-methylaminophenyl group, 3-dimethylaminophenyl group,3-(methanesulfonyl)methylaminophenyl group, 3-methylcarbonylaminophenylgroup, 3-methanesulfonylaminophenyl group,4-chloro-3-methanesulfonylaminophenyl group, 3-ethanesulfonylaminophenylgroup, 3-(propane-1-sulfonylamino)phenyl group,3-(propane-2-sulfonylamino)phenyl group,3-chloromethanesulfonylaminophenyl group,3-trifluoromethanesulfonylaminophenyl group,3-(2,2,2-trifluoroethanesulfonylamino)phenyl group,3-(2-methoxyethyl)methylaminophenyl group, 3-methylcarbonylaminophenylgroup, 3-ethylcarbonylaminophenyl group, 3-propylcarbonylaminophenylgroup, 3-isopropylcarbonylaminophenyl group, 3-ethoxycarbonylaminophenylgroup, 3-(hydroxymethylcarbonyl)aminophenyl group,3-(2-hydroxyethylcarbonylamino)phenyl group,3-ethylaminocarbonylaminophenyl group,3-(2-dimethylaminoethylcarbonylamino)phenyl group,3-(3-dimethylaminopropylcarbonylamino)phenyl group,3-(methoxymethylcarbonylamino)phenyl group,3-(butylcarbonylaminomethylcarbonylamino)phenyl group,3-(2-butylcarbonylaminoethylcarbonylamino)phenyl group,3-methylaminocarbonylaminophenyl group,3-methoxyaminocarbonylaminophenyl group,3-dimethylaminocarbonylaminophenyl group,3-(dimethylaminomethylcarbonylamino)phenyl group,3-(2-morpholin-4-ylethylamino)phenyl group,3-(2-benzyloxycarbonylaminoethyl)sulfonylaminophenyl group,3-(2-aminoethyl)sulfonylaminophenyl group,3-(2-butylcarbonylaminoethyl)sulfonylaminophenyl group,3-dimethylaminosulfonylaminophenyl group, 3-carboxyphenyl group,3-carbamoylphenyl group, 3-methanesulfonylphenyl group,4-methanesulfonylphenyl group, 3-ethanesulfonylphenyl group,3-methylaminosulfonylphenyl group, 3-ethylaminosulfonylphenyl group,3-benzenesulfonylaminophenyl group, 3-aminosulfonylphenyl group,3-dimethylaminosulfonylphenyl group, 4-dimethylaminosulfonylphenylgroup, 3-(4-methylpiperazine-1-sulfonyl)phenyl group,3-(morpholine-4-sulfonyl)phenyl group, 3-(piperidine-1-sulfonyl)phenylgroup, 3-(pyrrolidine-1-sulfonyl)phenyl group,3-methylaminocarbonylphenyl group, 3-morpholin-4-ylphenyl group,3-pyrrolidin-1-ylphenyl group, 3-piperidin-1-ylphenyl group,3-(4-methylpiperazin-1-yl)phenyl group, 3-(2-oxopyrrolidin-1-yl)phenylgroup and 3-(3-oxomorpholin-4-yl)phenyl group can be mentioned.

As the “R⁶”,

wherein each symbol is as defined above, is preferable. Here, m ispreferably 0, the “ring Cy” is preferably C₃₋₁₂ carbon ring group andthe “carbon ring group” is preferably phenyl group (wherein the “C₃₋₁₂carbon ring group” and “phenyl group” are optionally substituted by 1 to5 substituents selected from group B, where the “group B” preferablyincludes the above-defined “halogen atom”, the above-defined “C₁₋₈ alkylgroup” and the above-defined “C₂₋₄ alkynyl group”).

Specifically, as the “R⁶”, 2-methoxyethyl group, 2,2-dimethylpropylgroup, 3-dimethylaminopropyl group, cyclopropyl group, cyclohexyl group,phenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenylgroup, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 4-bromophenylgroup, 2-fluorophenyl group, 4-fluorophenyl group, 4-iodophenyl group,o-tolyl group, p-tolyl group, 2-ethylphenyl group, 4-ethylphenyl group,2-propylphenyl group, 2-isopropylphenyl group, 4-isopropylphenyl group,2-butylphenyl group, 4-butylphenyl group, 2-isobutylphenyl group,4-tert-butylphenyl group, 2-(3-methylbutyl)phenyl group,4-trifluoromethylphenyl group, 4-(2-fluoroethyl)phenyl group,4-(2,2-difluoroethyl)phenyl group, 4-(2,2,2-trifluoroethyl)phenyl group,4-(1-ethylpropyl)phenyl group, 4-(1-propylbutyl)phenyl group,4-ethynylphenyl group, 2,4-difluorophenyl group, 2,6-difluorophenylgroup, 2,4-dichlorophenyl group, 4-bromo-2-fluorophenyl group,4-bromo-3-fluorophenyl group, 4-bromo-2-chlorophenyl group,4-chloro-2-fluorophenyl group, 2-fluoro-4-iodophenyl group,2-chloro-4-methylphenyl group, 4-chloro-2-methylphenyl group,4-bromo-2-methylphenyl group, 4-bromo-3-methylphenyl group,2-fluoro-4-methylphenyl group, 2-fluoro-4-trifluoromethylphenyl group,4-bromo-2-ethylphenyl group, 4-ethyl-2-fluorophenyl group,4-(2-carboxyethyl)-2-fluorophenyl group, 2-fluoro-4-propylphenyl group,2-fluoro-4-vinylphenyl group, 4-(2-carboxyvinyl)-2-fluorophenyl group,4-ethynyl-2-fluorophenyl group, 2-fluoro-4-(prop-1-ynyl)phenyl group,2-fluoro-4-(3-hydroxyprop-1-ynyl)phenyl group,2-fluoro-4-(3-methoxyprop-1-ynyl)phenyl group,4-cyclopropyl-2-fluorophenyl group,2-fluoro-4-(3-hydroxy-3-methylbut-1-ynyl)phenyl group,4-(3-dimethylaminoprop-1-ynyl)-2-fluorophenyl group,4-chloro-2-dimethylaminomethylphenyl group,4-dimethylamino-2-methylphenyl group, 4-hydroxyphenyl group,2-methoxyphenyl group, 4-methoxyphenyl group, 4-trifluoromethoxyphenylgroup, 4-isopropoxyphenyl group, 2,4-dimethoxyphenyl group,4-methoxy-2-methylphenyl group, 2-fluoro-4-methoxyphenyl group,4-bromo-2-hydroxyphenyl group, 4-bromo-2-methoxyphenyl group,2-bromo-4-methoxyphenyl group, 4-methylthiophenyl group,4-trifluoromethylthiophenyl group, 2-fluoro-4-methylthiophenyl group,4-aminophenyl group, 4-methylaminophenyl group, 2-dimethylaminophenylgroup, 3-dimethylaminophenyl group, 4-dimethylaminophenyl group,4-ethylaminophenyl group, 4-diethylaminophenyl group,4-ethylmethylamino-2-fluorophenyl group, 4-nitrophenyl group,4-cyanophenyl group, 6-aminopyridin-3-yl group,6-dimethylaminopyridin-3-yl group, 6-chloropyridin-2-yl group,4-chloropyridin-3-yl group, 4-carboxyphenyl group,4-methoxycarbonylphenyl group, 4-ethylaminophenyl group,4-(methylcarbonyl)methylaminophenyl group, 4-methanesulfonylphenylgroup, 4-trifluoromethanesulfonylphenyl group,4-dimethylamino-2-methylphenyl group, 4-dimethylamino-3-methylphenylgroup, 4-dimethylamino-3-trifluoromethylphenyl group,4-dimethylamino-2-propylphenyl group, 4-dimethylamino-2-fluorophenylgroup, 4-dimethylamino-3-fluorophenyl group, 4-dimethylphosphinoylphenyl group, benzo[1,3]dioxol-5-yl group, 1,1′-biphenyl-4-yl group,4-(piperidin-1-yl)phenyl group, 4-benzylphenyl group,4-(morpholin-4-yl)phenyl group, 1-methylpiperidin-4-yl group,1-isopropylpiperidin-4-yl group, thiazol-2-yl group,2-dimethylaminothiazol-4-yl group,1-methyl-1,2,3,4-tetrahydroquinolin-6-yl group, 1H-indol-5-yl group,1-methyl-1H-indol-5-yl group, 1-ethyl-1H-indol-5-yl group,1-methyl-1H-indol-6-yl group, 1-methyl-1H-indol-7-yl group,1,2-dimethyl-1H-indol-5-yl group, 1,2,3-trimethyl-1H-indol-5-yl group,6-20 fluoro-1H-indol-5-yl group, 1-methyl-1H-benzimidazol-5-yl group,1-methyl-1H-indazol-5-yl group, 1-methyl-2,3-dihydro-1H-indol-5-ylgroup, benzo[b]thiophen-5-yl group, 4-chlorobenzyl group, 2-bromobenzylgroup, 3-bromobenzyl group, 4-bromobenzyl group, 5-bromo-2-fluorobenzylgroup, 2-morpholin-4-ylethyl group and pyridin-3-ylmethyl group arepreferable.

More preferably, phenyl group, 2-chlorophenyl group, 3-chlorophenylgroup, 4-chlorophenyl group, 2,4-dichlorophenyl group,3,4-dichlorophenyl group, 4-bromophenyl group, 2-fluorophenyl group,4-fluorophenyl group, 4-iodophenyl group, o-tolyl group, p-tolyl group,2-ethylphenyl group, 4-ethylphenyl group, 2-propylphenyl group,2-isopropylphenyl group, 4-isopropylphenyl group, 2-butylphenyl group,4-butylphenyl group, 2-isobutylphenyl group, 4-tert-butylphenyl group,2-(3-methylbutyl)phenyl group, 4-trifluoromethylphenyl group,4-(2-fluoroethyl)phenyl group, 4-(2,2-difluoroethyl)phenyl group,4-(2,2,2-trifluoroethyl)phenyl group, 4-(l-ethylpropyl)phenyl group,4-(1-propylbutyl)phenyl group, 4-ethynylphenyl group, 2,4-difluorophenylgroup, 2,6-difluorophenyl group, 2,4-dichlorophenyl group,4-bromo-2-fluorophenyl group, 4-bromo-3-fluorophenyl group,4-bromo-2-chlorophenyl group, 4-chloro-2-fluorophenyl group,2-fluoro-4-iodophenyl group, 2-chloro-4-methylphenyl group,4-chloro-2-methylphenyl group, 4-bromo-2-methylphenyl group,4-bromo-3-methylphenyl group, 2-fluoro-4-methylphenyl group,2-fluoro-4-trifluoromethylphenyl group, 4-bromo-2-ethylphenyl group,4-ethyl-2-fluorophenyl group, 4-(2-carboxyethyl)-2-fluorophenyl group,2-fluoro-4-propylphenyl group, 2-fluoro-4-vinylphenyl group,4-(2-carboxyvinyl)-2-fluorophenyl group, 4-ethynyl-2-fluorophenyl group,2-fluoro-4-(prop-1-ynyl)phenyl group,2-fluoro-4-(3-hydroxyprop-1-ynyl)phenyl group,2-fluoro-4-(3-methoxyprop-1-ynyl)phenyl group,4-cyclopropyl-2-fluorophenyl group,2-fluoro-4-(3-hydroxy-3-methylbut-1-ynyl)phenyl group,4-(3-dimethylaminoprop-1-ynyl)-2-fluorophenyl group,4-chloro-2-dimethylaminomethylphenyl group,4-dimethylamino-2-methylphenyl group, 4-hydroxyphenyl group,2-methoxyphenyl group, 4-methoxyphenyl group, 4-trifluoromethoxyphenylgroup, 4-isopropoxyphenyl group, 2,4-dimethoxyphenyl group,4-methoxy-2-methylphenyl group, 2-fluoro-4-methoxyphenyl group,4-bromo-2-hydroxyphenyl group, 4-bromo-2-methoxyphenyl group,2-bromo-4-methoxyphenyl group, 4-methylthiophenyl group,4-trifluoromethylthiophenyl group, 2-fluoro-4-methylthiophenyl group,4-aminophenyl group, 4-methylaminophenyl group, 2-dimethylaminophenylgroup, 3-dimethylaminophenyl group, 4-dimethylaminophenyl group,4-ethylaminophenyl group, 4-diethylaminophenyl group,4-ethylmethylamino-2-fluorophenyl group, 4-nitrophenyl group,4-cyanophenyl group, 6-aminopyridin-3-yl group,6-dimethylaminopyridin-3-yl group, 6-chloropyridin-2-yl group,4-chloropyridin-3-yl group, 4-carboxyphenyl group,4-methoxycarbonylphenyl group, 4-ethylaminophenyl group,4-(methylcarbonyl)methylaminophenyl group, 4-methanesulfonylphenylgroup, 4-trifluoromethanesulfonylphenyl group,4-dimethylamino-2-methylphenyl group, 4-dimethylamino-3-methylphenylgroup, 4-dimethylamino-3-trifluoromethylphenyl group,4-dimethylamino-2-propylphenyl group, 4-dimethylamino-2-fluorophenylgroup, 4-dimethylamino-3-fluorophenyl group, 4-dimethylphosphinoylphenylgroup, 1,1′-biphenyl-4-yl group, 4-(piperidin-1-yl)phenyl group,4-benzylphenyl group and 4-(morpholin-4-yl)phenyl group can bementioned.

As the “R³”, preferably, C₁₋₆ alkyl group (wherein the C₁₋₆ alkyl groupis optionally substituted by 1 to 3 substituents selected from group A)can be mentioned.

Specifically, a hydrogen atom, methyl group, ethyl group, propyl group,isobutyl group, 2-methoxyethyl group, cyclopropyl group,2-dimethylaminoethyl group and 2-propenyl group are preferable, andmethyl group is particularly preferable.

As the “R⁴”, preferably, a C₁₋₆ alkyl group (wherein the C₁₋₆ alkylgroup is optionally substituted by 1 to 3 substituents selected fromgroup A) can be mentioned.

Specifically, a hydrogen atom, methyl group, propyl group and hydroxygroup are preferable, and methyl group is particularly preferable.

As the “R⁵”, a hydrogen atom and methyl group are preferable, and ahydrogen atom is particularly preferable.

The “pharmaceutically acceptable salt thereof” may be any 20 salt aslong as it forms a non-toxic salt with the compounds of theabove-mentioned formula [I], [I′] and [I-1]-[I-3] and can be obtained bya reaction with an inorganic acid such as hydrochloric acid, sulfuricacid, phosphoric acid, hydrobromic acid and the like; an organic acidsuch as oxalic acid, malonic acid, citric acid, fumaric acid, lacticacid, malic acid, succinic acid, tartaric acid, acetic acid,trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonicacid, benzenesulfonic acid and the like; an inorganic base such assodium hydroxide, potassium hydroxide, calcium hydroxide, magnesiumhydroxide, ammonium hydroxide and the like; an organic base such asmethylamine, diethylamine, triethylamine, triethanolamine,ethylenediamine, tris(hydroxymethyl)methylamine, guanidine, choline,cinchonine and the like; or an amino acid such as lysine, arginine,alanine and the like. The present invention also encompasses hydrate andsolvate of each compound.

The present invention also encompasses prodrugs and metabolites of eachcompound.

By the “prodrug” is meant a derivative of the compound of the presentinvention, which has a chemically or metabolically decomposable groupand which, after administration to a body, restores to the originalcompound to show its inherent efficacy, including a complex and a salt,not involving a covalent bond.

The prodrug is utilized for, for example, improving absorption by oraladministration or targeting of a target site.

As the site to be modified, highly reactive functional groups in thecompound of the present invention, such as hydroxyl group, carboxylgroup, amino group, thiol group and the like, are mentioned.

For example, a compound wherein a hydroxyl group is substituted by—CO-alkyl, —CO₂-alkyl, —CONH-alkyl, —CO-alkenyl, —CO₂-alkenyl,—CONH-alkenyl, —CO-aryl, —CO₂-aryl, —CONH-aryl, —CO-heterocycle,—CO₂-heterocycle, —CONH-heterocycle (wherein alkyl, alkenyl, aryl andheterocycle are optionally substituted by halogen atom, alkyl group,hydroxyl group, alkoxy group, carboxy group, amino group, amino acidresidue, —PO₃H₂, —SO₃H, —OPO₃H₂, —OSO₃H and the like) or —PO₃H₂ and thelike, a compound wherein an amino group is substituted by —CO— alkyl,—CO₂-alkyl, —CO-alkenyl, —CO₂-alkenyl, —CO₂-aryl, —CO-aryl,—CO-heterocycle, —CO₂-heterocycle (wherein alkyl, alkenyl, aryl andheterocycle are optionally substituted by halogen atom, alkyl group,hydroxyl group, alkoxy group, carboxy group, amino group, amino acidresidue, —PO₃H₂, —SO₃H, —OPO₃H₂, —OSO₃H and the like) or —PO₃H₂ and thelike and the like can be mentioned.

Specifically, as the modifying group of hydroxyl group, acetyl group,propionyl group, isobutyryl group, pivaloyl group, palmitoyl group,benzoyl group, 4-methylbenzoyl group, dimethylcarbamoyl group,dimethylaminomethylcarbonyl group, sulfo group, alanyl group, fumarylgroup and the like can be mentioned. The sodium salt of 3-carboxybenzoylgroup or 2-carboxyethylcarbonyl group and the like can be alsomentioned.

Specifically, as the modifying group of carboxyl group, methyl group,ethyl group, propyl group, isopropyl group, butyl group, isobutyl group,tert-butyl group, pivaloyloxymethyl group, carboxymethyl group,dimethylaminomethyl group, 1-(acetyloxy)ethyl group,1-(ethoxycarbonyloxy)ethyl group, 1-(isopropyloxycarbonyloxy)ethylgroup, 1-(cyclohexyloxycarbonyloxy)ethyl group, carboxylmethyl group,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, benzyl group, phenylgroup, o-tolyl group, morpholinoethyl group, N,N-diethylcarbamoylmethylgroup, phthalidyl group and the like can be mentioned.

Specifically, as the modifying group of amino group, tert-butyl group,docosanoyl group, pivaloylmethyloxy group, alanyl group, hexylcarbamoylgroup, pentylcarbamoyl group, 3-methylthio-1-(acetylamino)propylcarbonylgroup, 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group,(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl group, tetrahydrofuranylgroup, pyrrolidylmethyl group and the like can be mentioned.

The “tumor” used in the present specification includes malignant tumor,and the “antitumor agent” contains an anticancer agent and is a compoundhaving an antitumor activity.

The compound of the present invention can be administered to a mammal(human, mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkeyetc.) and the like as an antitumor agent and the like.

When the compound of the present invention is used as a pharmaceuticalpreparation, it is generally admixed with pharmaceutically acceptablecarriers, excipients, diluents, extending agents, disintegrants,stabilizers, preservatives, buffers, emulsifiers, flavoring agents,coloring agents, sweetening agents, thickeners, corrigents, dissolutionaids, and other additives, that are known per se, such as water,vegetable oil, alcohol (e.g., ethanol, benzyl alcohol etc.),polyethylene glycol, glycerol triacetate, gelatin, carbohydrate (e.g.,lactose, starch etc.), magnesium stearate, talc, lanolin, petrolatum andthe like, formed into tablet, pill, powder, granule, suppository,injection, eye drop, liquid, capsule, troche, aerosol, elixir,suspension, emulsion, syrup and the like by a conventional method, andadministered systemically or topically, and orally or parenterally.

While the dose varies depending on age, body weight, symptom, treatmenteffect, administration method and the like, it is generally 0.01 mg to 1g once for an adult, which is given once to several times a day orallyor in a dosage form of an injection such as intravenous injection andthe like.

An antitumor agent is generally required to sustain its effect for along time, so that can be effective not only for temporal suppression ofthe proliferation of cancer cells but also for the prohibition of there-prohibition of cancer cells. This means that a prolongedadministration is necessary and that a high single dose may befrequently inevitable to sustain effect for a longer period through thenight. Such prolonged and high dose administration increases the risk ofcausing side effects.

In view of this, one of the preferable embodiments of the pyrimidinecompound of the present invention is such compound as permitting highabsorption by oral administration, and such compound capable ofmaintaining blood concentration of the administered compound for anextended period of time.

A compound capable of showing p15 protein induction and/or p27 proteininduction and/or MEK inhibition in combination is preferable.

This compound is useful for the treatment of diseases caused byundesirable cell proliferation.

As the “diseases caused by undesirable cell proliferation”, for example,tumor, specifically cerebral tumor (neuroglioma having a component ofmalignant astroglioma and oligodendroglioma and the like), cancer ofesophangus, stomach cancer, liver cancer, pancreatic cancer, colorectalcancer (colon cancer, rectal cancer etc.), lung cancer (non-small celllung cancer, small cell lung cancer, primary and metastatic squamouscancer etc.), renal cancer, breast cancer, ovarian cancer, prostatecancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma,osteosarcoma, seminoma, extragonadal tumor, testicle tumor, uterinecancer (cervical cancer, endometrial cancer and the like), head and necktumor (maxillary cancer, larynx cancer, pharyngeal cancer, lingualcancer, intraoral cancer and the like), multiple myeloma, malignantlymphoma (reticulosarcoma, lymphosarcoma, Hodgkin's disease etc.),polycythemia vera, leukemia (acute myeloid leukemia, chronic myeloidleukemia, acute lymphocytic leukemia, chronic lymphocytic leukemiaetc.), goiter, renal pelvic cancer, ureteral tumor, bladder tumor,gallbladder cancer, bile duct cancer, chorioma, malignant melanoma,pediatric tumor (sarcoma of the ewing's family, Wilms' tumor,rhabdomyosarcoma, vascular sarcoma, embryonal testicle cancer,neuroblastoma, retinoblastoma, hepatoblastoma, nephroblastoma etc.) andthe like can be mentioned.

Application to cerebral tumor (neuroglioma having a component ofmalignant astroglioma and oligodendroglioma etc.), cancer of esophangus,stomach cancer, liver cancer, pancreatic cancer, colorectal cancer(colon cancer, rectal cancer etc.), lung cancer (non-small cell lungcancer, small cell lung cancer etc.), renal cancer, breast cancer,ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma andthe like can be mentioned. more preferably, colon cancer, pancreascancer, renal cancer, lung cancer, and breast cancer is preferable, andapplication to colon cancer and pancreas cancer is particularlypreferable.

In addition, treatment of chronic pain, specifically, neuropathic pain,catapletic pain, pain associated with chronic alcoholism, vitamindeficiency, uremia and hypothyroidism can be mentioned. Furthermore,neutrophile-mediated disease or symptoms, specifically, ischemiareperfusion injury, chronic obstructive pulmonary disease, acuterespiratory disease syndrome, cystic fibrosis, catapletic pulmonaryfibrosis, sepsis, endotoxemia, lung emphysema and pulmonary asbestosiscan be mentioned. Furthermore, graft rejection can be mentioned.Moreover, arthritis, specifically, rheumatoid arthritis andosteoarthritis can be mentioned. In addition, asthma can be mentioned.Moreover, viral diseases, specifically, herpes virus (HSV-1) infection,human cytomegalovirus (HCMV) infection, human immunodeficiency virus(HIV) infection can be mentioned. Furthermore, disease caused bydenaturation or injury of cartilage, specifically, osteoarthrosis,rheumatoid arthritis, osteochondrosis dissecans and disease requiringchondrogenesis can be mentioned.

Besides the above, application to restenosis, psoriasis,atherosclerosis, cardiac failure, apoplexia and the like can bementioned.

As the “diseases caused by undesirable cell proliferation”, tumor andrheumatism are preferable.

As other “antitumor agent” used for multiple drug therapy, alkylatingagent, platinum complex, metabolism antagonist, antibiotics, plantalkaloid, interferon, cyclooxygenase-2 (COX-2) inhibitor, hormonalanticancer agent, cancer cell vaccine, bacterial preparation, mushroomextract polysaccharides, cytokine agonist, interleukin preparation,antibody drug, immunomodulator, angiogenesis inhibitor, intracellulartube formation inhibitor, cell proliferation inhibitor, cell cycleregulator, apoptosis inducer, cancer gene therapy agent and the like canbe mentioned.

As the alkylating agent, cyclophosphamide, ifosfamide, melpharan,buslfan, nimustine, ranimustine (MCNU), nitrogen mustard-N-oxidehydrochloride, thiotepa, procarbazine hydrochloride, carboquone,mitobronitol, improsulfan tosylate, 20 estramustine phosphate sodium,dacarbazine, temozolomide, dacarbazine (DTIC), mustine hydrochride,treosulfan, temozolomide, MS-247, (−)-(S)-bromofosfamide and the likecan be mentioned.

As the platinum complex, cisplatin, carboplatin, 25 nedaplatin,paraplatin, etoposide, Oxaliplatin, eptaplatin, miriplation, lobaplatin,picoplatin, oxaliplatin, satraplatin, SLIT-cisplatin and the like can bementioned.

As the metabolism antagonist, methotrexate, 6-mercaptopurine,cytosine-arabinoside, enocitabine (BHAC), 5-fluorouracil, tegafur,tegafur-uracil (UFT), carmofur (HCFU), doxifluridine, gemcitabinehydrochloride, hydroxyl carbamide, procarbazine hydrochloride,pemetrexed disodium, L-MDAM, mercaptopurine riboside, fludarabinephosphate, tegafur-gimestat-otastat, levofolinate-fluorouracil, folinatecalcium levofolinate, bemcitabine, calcium levolecucovorin,capecitabine, cytarabine, cytarabine ocfosfate, CS-682,3′-ethynylcytidine, TAS-102, capecitabine, fulvestrant, idoxuridine,hydroxyurea, pemetrexeddisodium, 3-AP, benspm, lometrexol,troxacitabine, ABT-510, AP-2/09, AR-726, AVI-4126, belimumab, CA4P,colorectal cancer vaccine, COU-1, degarelix, DJ-927, DPC-974, EKB-569,enzastaurin hydrochloride, fentanyl citrate, fulvestrant, galliummaltolate, HuMax-EGFR, IDD-1, LE-AON, MDX-070, MT-201, NK-911, NV-07,Oncomyc-NG, pertuzumab, PX-103.1, renal cancer vaccine, SN-4071, TL-139,topixantrone dihydrochloride, ZYC-101a and the like can be mentioned.

As the antibiotics, actinomycin D, daunomycin, doxorubicin (adriamycin),epirubicin, aclacinomycin A, mitomycin C, bleomycin, pirarubicinhydrochloride, idarubicin hydrochloride, aclarubicin hydrochloride,amrubicin hydrochloride, peplomycin sulfate, neocarzinostatine,zinostatin stimalamer, valrubicin, liposormal doxorubicin, NK911,BMS-247550(epothilone derivative), KRN5500, KW-2170, annamycin,becatecarin, PK1, sabarubicin hydrochloride, CVS-10290 and the like canbe mentioned.

As the plant alkaloid, vincristine, vinblastine, vindesine, etoposide,docetaxel, paclitaxel, irinotecan hydrochloride, vinorelbine tartrate,mitoxantrone hydrochloride, noscapine, vinflunine, docetaxel, E-7010,polyglutamated paclitaxel, soblidotin, Bay59-8862, E-7389, DJ-927,HTI-286, AC-7700, T-3782, ABI-007, batabulin sodium, DHA-paclitaxel,deoxyepothilone B, ixabepilone, MBT-0206, ortataxel, SB-715992, AI-850,synthadotin, ixabepilone, rubitecan, nogitecan hydrochloride, topotecanhydrochloride, sobuzoxane, etoposide phosphate disodium salt,dexrazoxane hydrochloride, rubitecan IST-622, exatecan mesylate, TOP-53,edotecarin, karenitecan, AG-7352, TAS-103, T-0128, NK-314, CKD-602,BNP-1350, lurtotecan, pegamotecan, rubitecan, LE-SN38, CPT-11 and thelike can be mentioned.

As interferon, interferon α, interferon α-2a, interferon α-2b,interferon β and interferon γ, interferon γ-1a, interferon γ-1b,interferon γ-n1 and the like can be mentioned.

As the cyclooxygenase-2 inhibitor, rofecoxib, celecoxib, lumiracoxib,tiracoxib (tilmacozib), CS-502, CS-706, valdecoxib, parecoxib, R-109339,deguelin, ajulemic acid, p-54, E-6087, LM-4108, R-109339, CBX-AC,CBX—PR, CBX-BU, L-748706, DMNQ-S64, ON-09250, ON-09300 and the like canbe mentioned.

As the hormonal anticancer agent, leuprorelin acetate, goserelinacetate, aminoglutethimide, triptorelin, goserelin, formestane,fabrozole monohydrochloride, letrozole, exemestane, deslorelin,buserelin acetate, cetrorelix acetate, histrelin acetate, abarelix,atrigel-leuprolide, estramustine phosphate sodium, chlormadinoneacetate, fosfetrol, flutamide, bicartamide, cyproterone acetate,medroxyprogesterone acetate, tamoxifen citrate, toremifene citrate,mepithiostane, epithiostanol, medroxyprogesterone acetate, fluvestrant,ormeloxifene, raloxifene hydrochloride, miproxifene phosphate, TAS-108,FMPA, fadrozole, anastrozole, exemestan, letrozole, formestane,bosentan, atrasentan, dutasteride, ESI, KT5555, KAT-682 and the like canbe mentioned.

As the cancer cell vaccine, cancer vaccine, activated lymphocyte, UL56deficient HSV, vaccine for colorectal cancer treatment, cancer peptidevaccine and the like can be mentioned.

As the bacterial preparation, BCG, anti-malignant tumor streptococcalpreparation, LC9018, tubercle bacillus hot water an extract and the likecan be mentioned.

As the mushroom extract polysaccharides, lentinan, Coriolus versicolorpolysaccharides (krestin), sizofiran, CM6271 and the like can bementioned.

As the cytokine agonist, ubenimex and the like can be mentioned.

As the interleukin preparation, interleukin-2, teceleukin,interleukin-12 and the like can be mentioned. As the antibodypharmaceutical agent, immunomodulator, trastuzumab, rituximab,gemtuzumab ozogamicin, iburitumomab tiuxetan, cetuximab, bevacizumab,caprpmab pendetide, capromab pendetide indium, pemetrexed disodium,yttrium 90 ibritumab tiuxetan, votumumab, humanized IL-6 receptorantibody, anti-TA226 human monoclonal antibody, F(ab′) human antibodyGAH, EMD72000, partuzumab, alemtuzumab, VEGF receptor FLt-1 antibody,KW-2871, humanized anti-GM2 antibody, humanized anti-GD2 antibody,KM2760, TRAIL receptor-2 monoclonal antibody, anti-TRAIL receptor DR5antibody, TRAIL-RImAb, humanized anti-HM1.24 antibody, humanized FasLantibody, humanized anti-CD26 monoclonal antibody, α-galactosylceramide,diphtheria toxin modified transferrin bond, CD47 monoclonal antibody,anti-human melanoma monoclonal antibody, HoAKs-1 (anti-lung cancermonoclonal antibody) and the like can be mentioned.

As the angiogenesis inhibitor, gefitinib (Iressa), thalidomide,cetuximab, semaxanib, TSU-68, KRN633, KRN951, marimastat, S-3304,erlotinib hydrochloride, ZD6474, GW572016, S-3304, E7820, SU6668, E7080,NK4, TAS-101, lapatinib, priomastat, RPI-4610, thalidomide, WX-UK1,2-methoxyestradiol, SG-292, FYK-1388 and the like can be mentioned.

As the intracellular tube formation inhibitor, TAC-01, E-7820 and thelike can be mentioned.

As the cell proliferation inhibitor, imatinib mesylate, trastuzumab,rituximab, gemtuzumab, AHM, mubritinib/TAK-165, KW-2871, KM8969,CP-724714 and the like can be mentioned.

As the cell cycle regulator, Boltezomib (NF-κβ Activation inhibitor),histone deacetylase HDAC inhibitor (FK-228, SAHA, CI-994, LAQ-824,pyroxamide, AN-9, PBA, MS-275 and the like), E-7070, flavopiritol,UCN-01, CGP41251, CCI-779, KT5555, HMN-214, Y-27632, vatalanib/PTK-787A,MGCD0130, temsirolirnus, (R)-roscovitine, indisulam and the like can bementioned.

As the apoptosis inducer, bortezomib, arglabin, R-115777, KW-2401,BMS-214662, tipifarnib, lonafarnib, arglabin, bexarotene, exisulind,glufosfamide, irofulven, MX-126374, MX-2167, GRN163, GM95, MST-312,(−)-EGCG(Teavigo) and the like can be mentioned.

As the cancer gene therapy agent, A-007, Ad/Q5-H-sDd, apaziquone,AVE-8062, MS-214662, combretastatin A-4, didox, dolastatin-10,ganglioside vaccine, GivaRex, ILX-23-7553, interleukins, itriglumide,KW-2401, MCC-465, miriplatin, MUC-1 vaccine, OSI-7904L, platelet factor4, SR-271425, ZK-230211 and the like can be mentioned.

As other antitumor agents, anticancer agents, L-asparaginase, tretinoin,levoleucovorin calcium, celmoleukin, 111ln-pentetreotide, ibandronatesodium hydrate, aminolevulinic acid hydrochloride, ukrain, Stem cellfactor, denileukin difftitox, menatetrenone, methoxsalen, trimetrexateglucuronate, IOR-R3, everolimus, cytokeratin 19, doxercalciferol,alitretionoin, bexarotene, verteporfin, morphine sulfatesustained-release, Bacillus Calmette Guerin, megestrol acetate,menadione, floxuridine, thyrotropin alfa, inositol hexaphosphate,augmerosen, Thio TEPA, chorionic gonadotropin, histaminedihydrochloride, lycopene, talaporfin sidium, tasonermin, arsenictrioxide, levamisole hydrochroride, folic acid, teniposide, mebendazole,morphine hydrochloride, ALA Me ester, anethole dithiolethion,testosterone propionate, cinacalcet hydrochloride, anetholedithiolethione, testosterone, mitotane, sodium thiosulfate, zevalin,bexxar, salmon calcitonin, novobiocin, aminoglutethimide, eflornithinehydrochloride, lonidamine, amoxnox, pirarubicin, vesnarinone,pamidronate sodium, clodronate disodium, zoledronic acid monohydrate,ambamustine hydrochloride, ubestatin, amifostine hydrate,deoxyspergualin hydrochloride, pentostatin, bisantrene, peplomycin,iobenguane, amsacrine, trilostane, tramadol hydrochloride, elliptiniumacetate, ladakamycin, bromebrate sodium, nitracrin dihydrochloridehydrate, altretamine, OROS-oxyodone, fentanyl citrate, aspirin, AERxMorphine sulfate, carmustine, metoclopramide hydrochloride, loperamidehydrochloride, nilutamide, polysaccharide K, ranimustine, atvogen,pipobroman, imiquimod (interferon inducers), cladribine, tibolone,suramin sodium, leflunomide, fentanyl, octreotide acetate, inositol,ursodiol, feverfew, lentinan, tetranabinex, (cannabinoid receptoragonists), pegaspargase, triclosan, crbohydrate antigen 19-9,angiopeptin acetate, fotemustine, gallium nitrate, trabectebin,raltitrexed, zinostatin stimalamer, hexadecylphosphocholine, tazarotene,finasteride, clofarabine, temoporfin, SY-801, human angiotensin II,efaproxiral sodium, amonafide (DNA-Intercalating Drug), SP-1053C(DNA-Intercalating Drug), antineoplaston AS2-1, fenretinide (retinoids),trabectebin, mammastatin, DOS-47, ECO-04601, thymectacin, rhIGFBP-3,carboxyamidotriazole, CoFactor, davanat-1, tariquidar, ONT-093,minobronic acid, minodronic acid, dofequidar fumarate (MDR-1inhibitors), tariquidar (MDR-1 Inhibitors), Davanat-1, ranpirnase,atrasentan, meclinertant, tacedinline, troxacitabine, DN-101, EB-1627,ACO-04601, MX-116407, STA-4783, Davanat-1, moverastin, mitoxantronehydrochloride, procarbazine hydrochloride, octreotide acetate, porfimersodium, pentostatin, cladribine, sobuzoxane, tretinoin, aceglatone,mitotane, porfimer sodium, elliptinium Acetate, AZD6126, tirapazamine,Bay4.3-9006, tipifarnib/R115777, midostaurin, BMS-214662, EKB-569,E7107, CBP501, HMN-214, FK-866, WF-536, SU-11248, MKT-077, phenoxodiol,NSC-330507, G-CSF, Edrecolomab (Monoclonal Antibodies), satumomab,sargramostin (GM-CSF), tamibarotene (retinoid derivative), arsenictrioxide, dutasteride, menatetrenone, ZD4054, NIK-333, NS-9, ABT-510,S-2678, methioninase, TAS-105, metastin, TOP-008, NCO0-700, BCA and thelike can be mentioned.

As “other antitumor agents” used for the multiple drug therapy with thecompound of the present invention, platinum complex, alkylating agentand metabolism antagonist are preferable. It is possible to use 2 or 3or more pharmaceutical agents can be used in combination, wherein acombination of pharmaceutical agents having different action mechanismis one of the preferable embodiments. Moreover, selection ofpharmaceutical agents having non-overlapping side effects is preferable.

For a combined use of the compound of the present invention with “otherantitumor agents”, these two or more kinds of compounds may be containedin the same composition. In addition, a composition containing thecompound of the present invention and a composition containing “otherantitumor agents” may be simultaneously or sequentially administered.

When two agents are simultaneously administered, “simultaneous” includesadministration of 2 agents, with administration of one agent and thenthe other agent in several minutes after the first administration. By“sequentially” is meant a lapse of a given time. For example,administration of the other agent several minutes to several dozenminutes after the administration of the first agent, and administrationof the other agent several hours to several days after theadministration of the first agent are included, wherein the lapse oftime is not limited. For example, one agent may be administered once aday, and the other agent may be administered 2 or 3 times a day, or oneagent may be administered once a week, and the other agent may beadministered once a day and the like.

When the compound of the present invention is used as an antitumoragent, and when the compound of the present invention is used incombination with “other antitumor agents”, radiotherapy, activationlymphocyte therapy and the like may be further added.

Some examples of the Production Methods of the compound used forembodiment of the present invention are shown in the following. However,the Production Methods of the compound of the present invention are notlimited to these examples.

Even in the absence of description in the Production Methods, efficientproduction can be afforded by designs such as introducing, wherenecessary, a protecting group into a functional group followed bydeprotection in a subsequent step; subjecting a functional group to eachstep as a precursor and converting the group to a desired functionalgroup in a suitable step; exchanging the order of respective ProductionMethods and steps; and the like.

The work-up treatment in each step can be applied by a typical method,wherein isolation and purification is performed as necessary byselecting or combining conventional methods, such as crystallization,recrystallization, distillation, partitioning, silica gelchromatography, preparative HPLC and the like.

Production Method 1

wherein Hal is a halogen atom such as chlorine atom, bromine atom andthe like, R^(c1), R^(c2), R^(c3) and R^(c4) are the same or differentand each is a hydrogen atom or the above-defined “C₁₋₆ alkyl group”,R^(3′) is R³ other than a hydrogen atom, R^(c5) is a leaving group suchas a halogen atom, p-toluenesulfonyloxy, methanesulfonyloxy,trifluoromethanesulfonyloxy and the like, and other symbols are asdefined above.

Step 1

The compound [3] can be obtained by reacting compound [1] with compound[2] in a solvent preferably under a nitrogen atmosphere from cooling toroom temperature.

As the solvent, ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran (THF) and the like; hydrocarbonsolvents such as benzene, toluene, xylene, hexane and the like; and thelike can be mentioned.

Step 2

The compound [5] can be obtained by reacting compound [3] with compound[4] in a solvent preferably under a nitrogen atmosphere under heating.

As the solvent, acetic anhydride, acetyl chloride, phosphorusoxychloride and the like can be mentioned.

Step 3

Here, Hal is preferably bromine atom or chlorine atom. The compound [6]can be obtained by reacting compound [5] with a halogenating agent suchas phosphorus oxychloride, N-bromosuccinimide, N-iodosuccinimide and thelike, in a solvent such as trifluoromethanesulfonic acid, acetic acid,concentrated sulfuric acid, N,N-dimethylformamide (DMF), water and thelike, at room temperature to under heating.

Step 4

The compound [8] can be obtained by reacting compound [6] with compound[7] in a solvent under heating.

As the solvent, alcohol solvents such as water-containing or nonaqueousmethanol, ethanol and the like; ether solvents such as 1,4-dioxane,tetrahydrofuran (THF) and the like, and the like can be mentioned.

Step 5

The compound [10] can be obtained by reacting compound [8] with compound[9] in a solvent under heating.

As the solvent, ether solvents such as diphenylether and the like;acetic anhydride, acetyl chloride and the like can be mentioned.

Step 6

The compound [11] can be obtained by introducing a leaving group intocompound [10] by a conventional method.

For example, compound [11] can be obtained by reacting compound [10]with methanesulfonyl chloride, p-toluenesulfonyl chloride,trifluoromethanesulfonic anhydride and the like, in the presence of basesuch as trimethylamine hydrochloride, triethylamine, pyridine and thelike as necessary in a solvent.

As the solvent, acetonitrile; ether solvents such as tetrahydrofuran andthe like; halogen solvents such as dichloromethane and the like, and thelike can be mentioned.

Step 7

The compound [I-1-1] can be obtained by reacting compound [11] withcompound [12] under heating as necessary in a solvent.

As the solvent, N,N-dimethylacetamide, chloroform and the like can bementioned.

To improve reaction efficiency, 2,6-lutidine may be added.

Production Method 1-1

wherein each symbol is as defined above.

Step 1

The compound [14] can be obtained by reacting compound [1] with compound[13] in the same manner as in Production Method 1, Step 1.

Step 2

The compound [15] can be obtained by reacting compound [14] withcompound [4] in the same manner as in Production Method 1, Step 2.

Step 3

The compound [16] can be obtained by reacting compound [15] in the samemanner as in Production Method 1, Step 3.

Step 4

The compound [17] can be obtained by reacting compound [16] withcompound [7] in the same manner as in Production Method 1, Step 4.

Step 5

The compound [18] can be obtained by reacting compound [17] withcompound [9] in the same manner as in Production Method 1, Step 5.

Step 6

The compound [19] can be obtained by reacting compound [18] in the samemanner as in Production Method 1, Step 6.

Step 7

The compound [20] can be obtained by reducing compound [19] by aconventional method such as reduction with zinc or iron in a neutral oralkaline condition; iron and acid; tin or tin (II) chloride andconcentrated hydrochloric acid; alkali sulfide; alkaline hydrosulfiteand the like, or hydrogenation under hydrogen atmosphere and the like.

For example, compound [20] can be obtained by adding acetic acid andzinc powder to compound [19] under cooling to allow to react at roomtemperature. Alternatively, compound [20] can be obtained by addingpalladium-carbon to a solution of compound [19] in a mixed solvent ofTHF and methanol under hydrogen atmosphere to allow to react at roomtemperature.

Step 8

The compound [I-1-2] can be obtained by reacting compound [20] withcompound [12] in the same manner as in Production Method 1, Step 7.

Step 9

The compound [21] can be obtained by reacting compound [20] withmethanesulfonyl chloride in a solvent in the presence of base such astriethylamine, pyridine and the like under cooling.

As the solvent, acetonitrile; ether solvents such as tetrahydrofuran andthe like; halogen solvents such as dichloromethane and the like, and thelike can be mentioned.

Step 10

The compound [I-1-3] can be obtained by reacting compound [21] withcompound [12] in the same manner as in Production Method 1, Step 7.

Production Method 2

wherein R^(c6) is a hydrogen atom or an C₁₋₄ alkyl group, SR^(c7)(R^(c7) is lower alkyl such as methyl, ethyl and the like or benzyl) isa leaving group, and other symbols are as defined above.

Step 1

The compound [24] can be obtained by reacting compound [22] obtained inthe same manner as in Production Method 1, Step 1 to Step 4 withcompound [23].

Step 2

The compound [25] can be obtained by cyclizing compound [24] by aconventional method. For example, compound [25] can be obtained bystirring compound [24] in a solvent such as N,N-dimethylformamide andthe like in the presence of triethylamine at room temperature.

Step 3

The compound [26] can be obtained by reacting compound [25] with loweralkyl halide or benzyl halide in the presence of base.

As the base, potassium carbonate, sodium carbonate, lithium hydride,sodium hydride, potassium hydride and the like can be mentioned,potassium carbonate is preferable.

As the lower alkyl halide, methyl iodide, ethyl iodide, benzyl iodideand the like can be mentioned, methyl iodide is preferable.

Step 4

The compound [I-2] can be obtained by reacting compound [26] withcompound [12] in the same manner as in Production Method 1, Step 7.

Production Method 3

wherein R^(4′) is R⁴ other than a hydrogen atom, and other symbols areas defined above.

Step 1

The compound [28] can be obtained by reacting compound [1] with compound[27] in the same manner as in Production Method 1, Step 1.

Step 2

The compound [29] can be obtained by reacting compound [28] withcompound [4] in the same manner as in Production Method 1, Step 2.

Step 3

The compound [30] can be obtained by reacting compound [29] in the samemanner as in Production Method 1, Step 3.

Step 4

The compound [32] can be obtained by reacting compound [30] withcompound [31] in the same manner as in Production Method 1, Step 4.

Step 5

The compound [34] can be obtained by reacting compound [32] withcompound [33] in the same manner as in Production Method 1, Step 5.

Step 6

The compound [35] can be obtained by reacting compound [34] in the samemanner as in Production Method 1, Step 6.

Step 7

The compound [37] can be obtained by reacting compound [35] withcompound [36] in the same manner as in Production Method 1, Step 7.

Step 8

The compound [I-3-1] can be obtained by stirring compound [37] in asolvent, in the presence of base at room temperature to under reflux.

As the base, potassium carbonate, sodium carbonate, lithium hydride,sodium hydride, potassium hydride, sodium methoxide and the like can bementioned, potassium carbonate and sodium methoxide are preferable.

As the solvent, alcohol solvents such as methanol, ethanol, n-propanol,isopropanol and the like; mixed solvents of these solvent and amidesolvents such as N,N-dimethylformamide, N,N-dimethylacetamide and thelike, halogen solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane and the like or ether solvents such astetrahydrofuran (THF) and the like, and the like can be mentioned.

Production Method 4-1

wherein each symbol is as defined above.

Step 1

The compound [3] can be obtained by reacting compound [36] withcarbonyldiimidazole in a solvent in the presence of tertiary amine suchas triethylamine and the like under nitrogen or argon atmosphere fromcooling to room temperature, and then reacting with compound [1].

As the solvent, N,N-dimethylformamide, chloroform, dichloromethane,tetrahydrofuran and the like can be mentioned.

Step 2

The compound [39] can be obtained by acylating compound [3] withcompound [38] preferably under a nitrogen atmosphere by a conventionalmethod.

for example, when R^(°) c is hydrogen, compound [38] can be condensedwith compound [3] using acetic anhydride, acetyl chloride, pivaloylchloride, methanesulfonyl chloride and the like, particularlymethanesulfonyl chloride in a solvent such as N,N-dimethylformamide,N,N-dimethylacetamide and the like.

Step 3

The compound [40] can be obtained by reacting compound [39] in a solventin the presence of base at room temperature to under heating.

As the solvent, water, ethanol-water, tetrahydrofuran-water and the likecan be mentioned, water is preferable.

As the base, potassium carbonate, sodium carbonate, potassium hydroxide,sodium hydroxide, lithium hydride, sodium hydride, potassium hydride andthe like can be mentioned, sodium hydroxide is preferable.

Step 4

The compound [41] can be obtained by reacting compound [40] withN,N-dimethylformamide dimethylacetal in a N,N-dimethylformamide solventpreferably under a nitrogen atmosphere.

Step 5

The compound [42] can be obtained by reducing compound [41] by aconventional method.

For example, compound [42] can be obtained by treating with a reducingagent such as sodium borohydride, sodium cyanoborohydride and the likein an alcohol solvent such as methanol, ethanol, isopropanol,tert-butanol and the like or a mixed solvent thereof under a nitrogenatmosphere.

Step 6

The compound [43] can be obtained by reacting compound [42] withcompound [9] in the same manner as in Production Method 1, Step 5.

Step 7

The compound [44] can be obtained by reacting compound 5 [43] in thesame manner as in Production Method 1, Step 6.

Step 8

The compound [I-1-4] can be obtained by reacting compound [44] withcompound [12] in the same manner as in Production Method 1, Step 7.

Production Method 4-2

wherein each symbol is as defined above.

Step 1

The compound [28] can be obtained by reacting compound [45] withcompound [1] in the same manner as in Production Method 4-1, Step 1.

Step 2

The compound [46] can be obtained by reacting compound [28] withcompound [38] in the same manner as in Production Method 4-1, Step 2.

Step 3

The compound [47] can be obtained by reacting compound [46] in the samemanner as in Production Method 4-1, Step 3.

Step 4

The compound [48] can be obtained by reacting compound [47] in the samemanner as in Production Method 4-1, Step 4.

Step 5

The compound [49] can be obtained by reacting compound [48] in the samemanner as in Production Method 4-1, Step 5.

Step 6

The compound [50] can be obtained by reacting compound [49] withcompound [33] in the same manner as in Production Method 1, Step 5.

Step 7

The compound [51] can be obtained by reacting compound [50] in the samemanner as in Production Method 1, Step 6.

Step 8

The compound [52] can be obtained by reacting compound [51] withcompound [36] in the same manner as in Production Method 1, Step 7.

Step 9

The compound [I-3-2] can be obtained by reacting compound [52] in thesame manner as in Production Method 3, Step 8.

Production Method 4-3

wherein R^(c7) is a halogen atom such as bromine atom, chlorine atom andthe like or a hydroxyl group and the other symbols are as defined above.

Step 1

The compound [53] can be obtained by reacting compound [45] withcarbonyldiimidazole in a solvent in the presence of tertiary amine suchas triethylamine and the like under a nitrogen or argon atmosphere fromcooling to room temperature, and then reacting with ammonia.

As the solvent, N,N-dimethylformamide, chloroform, dichloromethane,tetrahydrofuran and the like can be mentioned.

Step 2

The compound [54] can be obtained by reacting compound [53] withcompound [38] in the same manner as in Production Method 4-1, Step 2.

Step 3

The compound [55] can be obtained by reacting compound [54] in the samemanner as in Production Method 4-1, Step 3. Step 4

The compound [56] can be obtained by reacting compound [55] in the samemanner as in Production Method 4-1, Step 4.

Step 5

The compound [57] can be obtained by introducing a protecting group intocompound [56] by a conventional method.

Step 6

The compound [58] can be obtained by reacting compound [57] in the samemanner as in Production Method 4-1, Step 5.

Step 7

The compound [59] can be obtained by reacting compound [58] withcompound [33] in the same manner as in Production Method 1, Step 5.

Step 8

The compound [60] can be obtained by reacting compound [59] in the samemanner as in Production Method 1, Step 6.

Step 9

The compound [61] can be obtained by reacting compound [60] withcompound [36] in the same manner as in Production Method 1, Step 7.

Step 10

The compound [62] can be obtained by reacting compound [61] in the samemanner as in Production Method 3, Step 8.

Step 11

The compound [63] can be obtained by deprotecting compound [62] by aconventional method.

Step 12

The compound [I-3-3] can be obtained by reacting compound [63] withcompound [64] by a conventional method.

For example, when R^(c7) is a hydroxyl group, compound [63] is reactedwith a condensing agent such as diethyl azodicarboxylate, diisopropylazodicarboxylate and the like and triphenylphosphine in a solvent suchas N,N-dimethylformamide, acetonitrile, tetrahydrofuran and the likeunder a nitrogen or argon atmosphere according to Mitsunobu reaction.

EXAMPLES Example 1 Synthesis ofN-{3-[5-(4-bromo-2-fluoro-phenylamino)-3-cyclopropyl-8-methyl-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidin-1-yl]phenyl}-methanesulfonamideStep 1 Synthesis of 1-cyclopropyl-3-(nitrophenyl)urea

To a solution of cyclopropylamine 1 (9 g) in tetrahydrofuran (250 ml)was added 3-nitrophenylisocyanate 2 (25 g) by small portions, and themixture was stirred at room temperature for 1 hr. The solid precipitatedfrom the reaction mixture was filtered by suction, washed with ethylacetate, and dried to give 1-cyclopropyl-3-(nitrophenyl)urea 3 (33 g,99%) as a yellow solid.

Step 2 Synthesis of1-cyclopropyl-3-(3-nitrophenyl)pyrimidine-2,4,6-trione

To 1-cyclopropyl-3-(nitrophenyl)urea 3 (33 g) obtained in Step 1 wereadded acetic anhydride (99 ml) and malonic acid 4 (17 g), and themixture was stirred under heating at 110° C. for 4 hrs. The reactionmixture was concentrated under reduced pressure. Chloroform was added tothe residue, and the mixture was stirred at room temperature for 10 min.Chloroform insoluble material was filtered by suction and dried to give1-cyclopropyl-3-(3-nitrophenyl)pyrimidine-2,4,6-trione 5 (28 g, 65%) asa brown solid.

Step 3 Synthesis of6-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione

To 1-cyclopropyl-3-(3-nitrophenyl)pyrimidine-2,4,6-trione 5 (28 g)obtained in Step 2 was added water (3 ml), phosphorus oxychloride (72ml) was added dropwise by small portions with stirring, and the mixturewas stirred with heating at 110° C. for 1 hr. The reaction mixture waspoured into ice water by small portions, and the precipitated solid wasfiltered by suction. The filtrate was dissolved in chloroform (300 ml),washed with water (30 ml) and brine (30 ml), and the organic layer wasdried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by column chromatography(chloroform:acetone=9:1) to give a 2:1 mixture (10 g, 34%) of6-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione 6 and4-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,6-dione 7 as awhite solid.

Step 4 Synthesis of3-cyclopropyl-6-methylamino-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione

To the mixture (30 g) of6-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione 6 and4-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,6-dione 7obtained in Step 3 were added ethanol (300 ml) and a 40% solution (150ml) of methylamine in methanol, and the mixture was stirred with heatingat 80° C. for 4.5 hrs, ice-cooled and the precipitated solid wasfiltered by suction. The residue was washed with water (1 liter) anddried to give3-cyclopropyl-6-methylamino-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione 8(16 g, 55%) as a white solid.

Step 5 Synthesis of3-cyclopropyl-5-hydroxy-8-methyl-1-(3-nitrophenyl)-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione

To 3-cyclopropyl-6-methylamino-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione8 (16 g) obtained in Step 4 were added diphenyl ether (160 ml) anddiethyl malonate 9 (40 ml), and the mixture was stirred under heating at230° C. for 11 hrs while evaporating the resulting ethanol. The reactionmixture was purified by column chromatography(chloroform→chloroform:acetone=9:1) to give3-cyclopropyl-5-hydroxy-8-methyl-1-(3-nitrophenyl)-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione10 (10 g, 51%) as a brown foamy oil.

Step 6 Synthesis of toluene-4-sulfonic acid3-cyclopropyl-8-methyl-1-(3-nitrophenyl)-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylester

To3-cyclopropyl-5-hydroxy-8-methyl-1-(3-nitrophenyl)-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione10 (18 g) obtained in Step 5 were added acetonitrile (180 ml), tosylchloride 11 (11 g) and triethylamine (8 ml), and the mixture was stirredwith heating under reflux at 110° C. for 1 hr. The reaction mixture wasconcentrated under reduced pressure. Water (100 ml) was added to theresidue and the mixture was extracted with chloroform (800 ml). Theorganic layer was washed with brine (50 ml), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas recrystallized from chloroform:diethyl ether=1:5 to givetoluene-4-sulfonic acid3-cyclopropyl-8-methyl-1-(3-nitrophenyl)-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester 12 (21 g, 82%) as a white solid.

Step 7 Synthesis of toluene-4-sulfonic acid1-(3-aminophenyl)-3-cyclopropyl-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester

To a suspension of toluene-4-sulfonic acid3-cyclopropyl-8-methyl-1-(3-nitrophenyl)-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester 12 (21 g) obtained in Step 6 in tetrahydrofuran was added stannouschloride dihydrate (45 g), and the mixture was stirred at roomtemperature for 4 hrs. The reaction mixture was alkalified withsaturated aqueous sodium hydrogen carbonate, an insoluble inorganicproduct was filtered off by suction using celite as a filtration aides,and the filtrate was extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography (chloroform:acetone=9:1) to give toluene-4-sulfonic acid1-(3-aminophenyl)-3-cyclopropyl-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester 13 (15 g, 74%) as a white solid.

Step 8 Synthesis of toluene-4-sulfonic acid3-cyclopropyl-1-(3-methanesulfonylaminophenyl)-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester

To toluene-4-sulfonic acid1-(3-aminophenyl)-3-cyclopropyl-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 13 (5 g) obtained in Step 7 was addedpyridine (40 ml), a solution of methanesulfonyl chloride 14 (0.9 ml) inchloroform (10 ml) was added dropwise with stirring under ice-cooling,and the mixture was stirred for 3 hrs in an ice bath. The reactionmixture was concentrated under reduced pressure, 2N hydrochloric acidwas added and the mixture was extracted with chloroform. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resultant solid was suspendedin diethyl ether:hexane=1:1, and filtered by suction to givetoluene-4-sulfonic acid3-cyclopropyl-1-(3-methanesulfonylaminophenyl)-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester 15 (5.5 g, 95%) as a white solid.

Step 9 Synthesis ofN-{3-[5-(4-bromo-2-fluoro-phenylamino)-3-cyclopropyl-8-methyl-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidin-1-yl]phenyl}-methanesulfonamide

To toluene-4-sulfonic acid3-cyclopropyl-1-(3-methanesulfonylaminophenyl)-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylester 15 (3.5 g) obtained in Step 8 was added 2-fluoro-4-bromoaniline 16(23 g), and the mixture was stirred under heating at 135° C. for 3 hrs.The reaction mixture was purified by column chromatography(chloroform:acetone=9:1) to giveN-{3-[5-(4-bromo-2-fluoro-phenylamino)-3-cyclopropyl-8-methyl-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidin-1-yl]phenyl}-methanesulfonamide17 (3.0 g, 83%) as a white solid.

MS ESI m/e: 590, 592 (M+H), 588, 590 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 0.99-1.08 (m, 2H), 2.66(s, 1H), 3.02 (s, 1H), 5.36 (s, 1H), 7.13 (d, J=9.0 Hz, 1H), 7.24-7.30(m, 2H), 7.43-7.54 (m, 3H), 7.74 (d, J=9.0 Hz, 1H), 10.00 (brs, 1H),10.53 (brs, 1H).

Examples 1-2 to 1-343

In the same manner as in Example 1-1, the compounds of Examples 1-2 to1-343 were obtained. The structural formulas thereof are shown in Tables1-1 to 1-58 with Example 1-1.

TABLE 1-1 Ex. No. structural formula 1-1

1-2

1-3

1-4

1-5

1-6

TABLE 1-2 Ex. No. structural formula   1-7

1-8

1-9

1-10

1-11

1-12

TABLE 1-3 Ex. No. structural formula 1-13

1-14

1-15

1-16

1-17

1-18

TABLE 1-4 Ex. No. structural formula 1-19

1-20

1-21

1-22

1-23

1-24

TABLE 1-5 Ex. No. structural formula 1-25

1-26

1-27

1-28

1-29

1-30

TABLE 1-6 Ex. No. structural formula 1-31

1-32

1-33

1-34

1-35

1-36

TABLE 1-7 Ex. No. structural formula 1-37

1-38

1-39

1-40

1-41

1-42

TABLE 1-8 Ex. No. structural formula 1-43

1-44

1-45

1-46

1-47

1-48

TABLE 1-9 Ex. No. structural formula 1-49

1-50

1-51

1-52

1-53

1-54

TABLE 1-10 Ex. No. structural formula 1-55

1-56

1-57

1-58

1-59

1-60

TABLE 1-11 Ex. No. structural formula 1-61

1-62

1-63

1-64

1-65

1-66

TABLE 1-12 Ex. No. structural formula 1-67

1-68

1-69

1-70

1-71

1-72

TABLE 1-13 Ex. No. structural formula 1-73

1-74

1-75

1-76

1-77

1-78

TABLE 1-14 Ex. No. structural formula 1-79

1-80

1-81

1-82

1-83

1-84

TABLE 1-15 Ex. No. structural formula 1-85

1-86

1-87

1-88

1-89

1-90

TABLE 1-16 Ex. No. structural formula 1-91

1-92

1-93

1-94

1-95

1-96

TABLE 1-17 Ex. No. structural formula 1-97 

1-98 

1-99 

1-100

1-101

1-102

TABLE 1-18 Ex. No. structural formula 1-103

1-104

1-105

1-106

1-107

1-108

TABLE 1-19 Ex. No. structural formula 1-109

1-110

1-111

1-112

1-113

1-114

TABLE 1-20 Ex. No. structural formula 1-115

1-116

1-117

1-118

1-119

1-120

TABLE 1-21 Ex. No. structural formula 1-121

1-122

1-123

1-124

1-125

1-126

TABLE 1-22 Ex. No. structural formula 1-127

1-128

1-129

1-130

1-131

1-132

TABLE 1-23 Ex. No. structural formula 1-133

1-134

1-135

1-136

1-137

1-138

TABLE 1-24 Ex. No. structural formula 1-139

1-140

1-141

1-142

1-143

1-144

TABLE 1-25 Ex. No. structural formula 1-145

1-146

1-147

1-148

1-149

1-150

TABLE 1-26 Ex. No. structural formula 1-151

1-152

1-153

1-154

1-155

1-156

TABLE 1-27 Ex. No. structural formula 1-157

1-158

1-159

1-160

1-161

1-162

TABLE 1-28 Ex. No. structural formula 1-163

1-164

1-165

1-166

1-167

1-168

TABLE 1-29 Ex. No. structural formula 1-169

1-170

1-171

1-172

1-173

1-174

TABLE 1-30 Ex. No. structural formula 1-175

1-176

1-177

1-178

1-179

1-180

TABLE 1-31 Ex. No. structural formula 1-181

1-182

1-183

1-184

1-185

1-186

TABLE 1-32 Ex. No. structural formula 1-187

1-188

1-189

1-190

1-191

1-192

TABLE 1-33 Ex. No. structural formula 1-193

1-194

1-195

1-196

1-197

1-198

TABLE 1-34 Ex. No. structural formula 1-199

1-200

1-201

1-202

1-203

1-204

TABLE 1-35 Ex. No. structural formula 1-205

1-206

1-207

1-208

1-209

1-210

TABLE 1-36 Ex. No. structural formula 1-211

1-212

1-213

1-214

1-215

1-216

TABLE 1-37 Ex. No. structural formula 1-217

1-218

1-219

1-220

1-221

1-222

TABLE 1-38 Ex. No. structural formula 1-223

1-224

1-225

1-226

1-227

1-228

TABLE 1-39 Ex. No. structural formula 1-229

1-230

1-231

1-232

1-233

1-234

TABLE 1-40 Ex. No. structural formula 1-235

1-236

1-237

1-238

1-239

1-240

TABLE 1-41 Ex. No. structural formula 1-241

1-242

1-243

1-244

1-245

1-246

TABLE 1-42 Ex. No. structural formula 1-247

1-248

1-249

1-250

1-251

1-252

TABLE 1-43 Ex. No. structural formula 1-253

1-254

1-255

1-256

1-257

1-258

TABLE 1-44 Ex. No. structural formula 1-259

1-260

1-261

1-262

1-263

1-264

TABLE 1-45 Ex. No. structural formula 1-265

1-266

1-267

1-268

1-269

1-270

TABLE 1-46 Ex. No. structural formula 1-271

1-272

1-273

1-274

1-275

1-276

TABLE 1-47 Ex. No. structural formula 1-277

1-278

1-279

1-280

1-281

1-282

TABLE 1-48 Ex. No. structural formula 1-283

1-284

1-285

1-286

1-287

1-288

TABLE 1-49 Ex. No. structural formula 1-289

1-290

1-291

1-292

1-293

1-294

TABLE 1-50 Ex. No. structural formula 1-295

1-296

1-297

1-298

1-299

1-300

TABLE 1-51 Ex. No. structural formula 1-301

1-302

1-303

1-304

1-305

1-306

TABLE 1-52 Ex. No. structural formula 1-307

1-308

1-309

1-310

1-311

1-312

TABLE 1-53 Ex. No. structural formula 1-313

1-314

1-315

1-316

1-317

1-318

TABLE 1-54 Ex. No. structural formula 1-319

1-320

1-321

1-322

TABLE 1-55 Ex. No. structural formula 1-323

1-324

1-325

1-326

1-327

1-328

TABLE 1-56 Ex. No. structural formula 1-329

1-330

1-331

1-332

TABLE 1-57 Ex. No. structural formula 1-333

1-334

1-335

1-336

1-337

1-338

TABLE 1-58 Ex. No. structural formula 1-339

1-340

1-341

1-342

1-343

Example 2-1 Synthesis of5-(4-chloro-phenylamino)-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trioneStep 1 Synthesis of 1,3-diphenyl-pyrimidine-2,4,6-trione

Acetic anhydride (290 ml) was added to 1,3-diphenylurea 18 (148 g),malonic acid 4 (81.6 g) was added under a nitrogen atmosphere, and themixture was stirred at 90° C. for 3 hrs. The mixture was stirred at 100°C. for 1.5 hrs and allowed to cool to room temperature. The reactionmixture was concentrated under reduced pressure. Ethanol (500 ml) wasadded to the residue, and the mixture was stirred at 90° C. When themixture was cooled to 40° C., the crystals were collected by filtration,washed with ethanol and dried to give1,3-diphenyl-pyrimidine-2,4,6-trione 19 (78.0 g, yield 40%).

Step 2 Synthesis of 6-chloro-1,3-diphenyl-1H-pyrimidine-2,4-dione

To 1,3-diphenyl-pyrimidine-2,4,6-trione 19 (78.0 g) obtained in Step 1was added water (16 ml). Phosphorus oxychloride (422 ml) was addeddropwise under stirring at room temperature over 50 min. After thecompletion of the dropwise addition, the mixture was stirred underheating at 110° C. for 3 hrs. After allowing to cool to roomtemperature, the reaction mixture was added to ice water by smallportions and the mixture was stirred at room temperature and extractedwith ethyl acetate. The organic layer was washed with brine andsaturated aqueous sodium hydrogen carbonate, and dried over anhydroussodium sulfate. Anhydrous sodium sulfate was filtered off and thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography (hexane:ethyl acetate=2:13:2) to give6-chloro-1,3-diphenyl-1H-pyrimidine-2,4-dione 20 (61.5 g, yield 74%) aspale-yellow crystals.

Step 3 Synthesis of 6-methylamino-1,3-diphenyl-1H-pyrimidine-2,4-dione

In the same manner as in Step 4 of Example 1-1 and using6-chloro-1,3-diphenyl-1H-pyrimidine-2,4-dione 20 (5.0 g) obtained inStep 2, ethanol (25 ml), a 40% solution (21.7 ml) of methylamine inmethanol, 6-methylamino-1,3-diphenyl-1H-pyrimidine-2,4-dione 21 (4.42 g,yield 90%) was obtained as colorless crystals.

Step 4 Synthesis of ethyl(6-methylamino-2,4-dioxo-1,3-diphenyl-1,2,3,4-tetrahydro-pyrimidine-5-thiocarbonyl)-carbamate

To 6-methylamino-1,3-diphenyl-1H-pyrimidine-2,4-dione 21 (1.18 g)obtained in Step 3 was added N,N-dimethylformamide (5.9 ml), ethylisothiocyanate formate 22 (0.52 ml) was added under a nitrogenatmosphere, and the mixture was stirred at room temperature for 1 hr.Water (30 ml) was added to the reaction mixture, and the crystals werecollected by filtration and washed with water to give crude ethyl(6-methylamino-2,4-dioxo-1,3-diphenyl-1,2,3,4-tetrahydro-pyrimidine-5-thiocarbonyl)-carbamate23 (1.68 g) as pale-yellow crystals, which were used for the next stepwithout purification.

Step 5 Synthesis of5-mercapto-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione

To crude ethyl(6-methylamino-2,4-dioxo-1,3-diphenyl-1,2,3,4-tetrahydro-pyrimidine-5-thiocarbonyl)-carbamate23 (1.58 g) obtained in Step 4 was added N,N-dimethylformamide (8.4 ml),triethylamine (0.63 ml) was added under a nitrogen atmosphere, and themixture was stirred at room temperature for 30 min. Water (25 ml) wasadded, the mixture was stirred, 1N hydrochloric acid (5.0 ml) was added,and the mixture was stirred at room temperature for 1 hr. The crystalswere collected by filtration, washed with water and dried to give crude5-mercapto-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione24 (1.53 g, over weight) as yellow crystals, which were used for thenext step without purification.

Step 6 Synthesis of8-methyl-5-methylsulfanyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione

To crude5-mercapto-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione24 (100 mg) obtained in Step 5 was added N,N-dimethylformamide (0.5 ml).Under a nitrogen atmosphere, potassium carbonate (44 mg) and methyliodide 25 (20 μl) were successively added, and the mixture was stirredat room temperature for 3 hrs. Water was added, and the mixture wasextracted with chloroform. The organic layer was washed with water andbrine, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfatewas filtered off, and the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography(hexane:ethyl acetate=4:1→3:1) to give8-methyl-5-methylsulfanyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione26 (91 mg, yield 89%) as brown crystals.

Step 7 Synthesis of5-(4-chloro-phenylamino)-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione

To8-methyl-5-methylsulfanyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione26 (149 mg) obtained in Step 6 was added toluene (2 ml), 4-chloroaniline27 (97 mg) was added, and the mixture was stirred under reflux for 3.5hrs. After allowing to cool to room temperature, diethyl ether wasadded. The crystals were collected by filtration, washed with diethylether and dried to give5-(4-chloro-phenylamino)-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione28 (94 mg, yield 53%) as colorless crystals.

MS ESI m/e: 472 (M+H), 470 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 2.68 (s, 3H), 7.34-7.39 (m, 2H), 7.41-7.61(m, 10H), 7.80-7.87 (m, 2H), 11.34 (s, 1H).

Example 2-2

In the same manner as in Example 2-1, the compounds of Example 2-2 wereobtained. The structural formulas thereof are shown in Table 2-1 withExample 2-1.

Table 2-1

TABLE 2-1 Ex. No. structural formula 2-1

2-2

Example 3-1 Synthesis of5-(4-bromo-phenylamino)-3-cyclopropyl-6,8-dimethyl-1-phenylamino-1H,6H-pyrido[4,3-d]pyrimidine-2,4,7-trione Step 1 Synthesis of1-(4-bromo-phenyl)-3-cyclopropyl-urea

Under a nitrogen atmosphere, tetrahydrofuran (80 ml) was added to4-bromophenyl isocyanate 30 (10.0 g), and a solution of cyclopropylamine1 (3.17 g) in tetrahydrofuran (20 ml) was added dropwise with stirringunder ice-cooling. After the completion of the dropwise addition, themixture was stirred at room temperature for 3 hrs, and the reactionmixture was concentrated under reduced pressure. Diethyl ether-hexane[1:1 (volume ratio), 100 ml] was added to the residue and, afterstirring, the crystals were collected by filtration and dried to give1-(4-bromo-phenyl)-3-cyclopropyl-urea 31 (12.9 g, over weight) ascolorless crystals, which were used for the next step withoutpurification.

Step 2 Synthesis of1-(4-bromo-phenyl)-3-cyclopropyl-pyrimidine-2,4,6-trione

To 1-(4-bromo-phenyl)-3-cyclopropyl-urea 31 (12.9 g) obtained in Step 1was added acetic anhydride (25.8 ml), malonic acid 4 (5.79 g) was addedunder a nitrogen atmosphere, and the mixture was stirred at 100° C. for3 hrs. After allowing to cool to room temperature, the reaction mixturewas concentrated under reduced pressure. Diethyl ether-ethanol [4:1(volume ratio), 100 ml] was added to the residue and, after stirring,the crystals were collected by filtration and dried to give1-(4-bromo-phenyl)-3-cyclopropyl-pyrimidine-2,4,6-trione 32 (11.9 g,yield 73%) as pale-yellow crystals.

Step 3 Synthesis of1-(4-bromo-phenyl)-6-chloro-3-cyclopropyl-1H-pyrimidine-2,4-dione

To 1-(4-bromo-phenyl)-3-cyclopropyl-pyrimidine-2,4,6-trione 32 (11.8 g)obtained in Step 2 was added water (1.31 ml) and phosphorus oxychloride(17.0 ml) was added dropwise with stirring at room temperature. Afterthe completion of the dropwise addition, the mixture was stirred at 110°C. for 3 hrs. After allowing to cool to room temperature, the reactionmixture was added to ice water by small portions and the mixture wasstirred. The mixture was stirred at room temperature and extracted withchloroform. The organic layer was washed with brine, and dried overanhydrous magnesium sulfate. Anhydrous magnesium sulfate was filteredoff, and the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography (hexane:ethylacetate=2:1→Tchloroform:acetone=30:1) to give a 1:1.4 mixture (11.6 g,yield 93%) of1-(4-bromo-phenyl)-6-chloro-3-cyclopropyl-1H-pyrimidine-2,4-dione 33 and3-(4-bromo-phenyl)-6-chloro-1-cyclopropyl-1H-pyrimidine-2,4,-dione 34 asa pale-yellow foamy oil.

Step 4 Synthesis of1-(4-bromo-phenyl)-3-cyclopropyl-6-methylamino-1H-pyrimidine-2,4-dione

A 1:1.3 mixture (5.34 g, yield 78%) of1-(4-bromo-phenyl)-3-cyclopropyl-6-methylamino-1H-pyrimidine-2,4-dione35 and3-(4-bromo-phenyl)-1-cyclopropyl-6-methylamino-1H-pyrimidine-2,4-dione36 was obtained as colorless crystals in the same manner as thesynthesis of compound 8 and using a 1:1.4 mixture (7.00 g) of1-(4-bromo-phenyl)-6-chloro-3-cyclopropyl-1H-pyrimidine-2,4-dione 33 and3-(4-bromo-phenyl)-6-chloro-1-cyclopropyl-1H-pyrimidine-2,4,-dione 34obtained in Step 3, ethanol (20.9 ml) and a 40% solution (10.5 ml) ofmethylamine in methanol.

Step 5 Synthesis of1-(4-bromo-phenyl)-3-cyclopropyl-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione

1-(4-Bromo-phenyl)-3-cyclopropyl-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione38 (0.40 g, yield 32%) was obtained as pale-yellow crystals in the samemanner as in Step 5 of Example 1-1 and using a 1:1.3 mixture (1.00 g) of1-(4-bromo-phenyl)-3-cyclopropyl-6-methylamino-1H-pyrimidine-2,4-dione35 and3-(4-bromo-phenyl)-1-cyclopropyl-6-methylamino-1H-pyrimidine-2,4-dione36 obtained in Step 4, 2-methyl-diethyl malonate 37 (2.56 ml) anddiphenyl ether (1.49 g).

Step 6 Synthesis of toluene-4-sulfonic acid1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester

To1-(4-bromo-phenyl)-3-cyclopropyl-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione38 (400 mg) obtained in Step 5 was added acetonitrile (8.0 ml), tosylchloride 11 (458 mg) and triethylamine (0.34 ml) were added under anitrogen atmosphere, and the mixture was stirred under reflux for 30hrs. After allowing to cool to room temperature, the mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (chloroform:acetone=25:1→20:1) to give toluene-4-sulfonicacid1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester 39 (407 mg, yield 74%) as ocher crystals.

Step 7 Synthesis of1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-5-phenylamino-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione

To toluene-4-sulfonic acid1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester 39 (100 mg) obtained in Step 6 was added aniline 40 (0.64 ml), andthe mixture was stirred at 150° C. for 2.5 hrs. After allowing to coolto room temperature, diethyl ether-hexane [1:1 (volume ratio), 30 ml]was added to the reaction mixture, and the crystals were collected byfiltration. The obtained crystals were purified by column chromatography(chloroform:acetone=15:1) to give1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-5-phenylamino-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione41 (81 mg, yield 93%) as pale-yellow crystals.

Step 8 Synthesis of5-(4-bromo-phenylamino)-3-cyclopropyl-6,8-dimethyl-1-phenylamino-1H,6H-pyrido[4,3-d]pyrimidine-2,4,7-trione

To1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-5-phenylamino-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione41 (78 mg) obtained in Step 7 was added chloroform-methanol [1:1 (volumeratio), 2.0 ml], potassium carbonate (22 mg) was added, and the mixturewas stirred at room temperature for 10 hrs. The mixture was furtherstirred under reflux for 3 hrs, and allowed to cool to room temperature.The mixture was concentrated under reduced pressure and purified bycolumn chromatography (chloroform:acetone=50:1) to give5-(4-bromo-phenylamino)-3-cyclopropyl-6,8-dimethyl-1-phenylamino-1H,6H-pyrido[4,3-d]pyrimidine-2,4,7-trione 42 (23 mg, yield 26%) ascolorless crystals.

MS ESI m/e: 493, 495 (M+H), 491, 493 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.77-0.82 (m, 2H), 1.09-1.15 (m, 2H), 1.36 (s,3H), 2.72-2.74 (m, 1H), 3.20 (s, 3H), 6.86 (d, 2H), 7.28-7.32 (m, 2H),7.34-7.51 (m, 5H), 11.36 (s, 1H).

Example 3-7 Synthesis ofN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamideStep 1 Synthesis ofN-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide

To trifluoromethanesulfonic acid3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester 43 (30.0 g) obtained in the same manner in Example 4-2, Step 6 tobe mentioned later and N-(3-aminophenyl)methanesulfonamide 44 (10.9 g)were added N,N-dimethylacetamide (60.0 ml) and 2,6-lutidine (6.82 ml),and the mixture was stirred at 130° C. for 3.5 hrs. After allowing tocool to room temperature, methanol (60 ml) was added with stirring andthe mixture was stirred for 2 hrs. The crystals were collected byfiltration and dried to giveN-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide45 (30.5 g, yield 96%) as colorless crystals.

Step 2 Synthesis ofN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide

Under a nitrogen atmosphere, to a solution (18.5 g) of 28% sodiummethoxide in methanol was added tetrahydrofuran (284 ml),N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide45 (28.4 g) obtained in Step 1 was added, and the mixture was stirred atroom temperature for 1 hr. Acetic acid (12.5 ml) was added, and themixture was stirred at room temperature for 1 hr and concentrated underreduced pressure. A 9:1 mixed solvent (426 mL) of 1-butanol and waterwas added to the obtained solid, and the mixture was stirred withheating under reflux for 3 hrs. The mixture was allowed to return toroom temperature and stirred overnight, and the crystals were collectedby filtration and dried. A 9:1 mixed solvent (426 mL) of 1-butanol andwater was added again to the obtained crystals, and the mixture wasstirred with heating under reflux for 3 hrs. The mixture was allowed toreturn to room temperature and stirred overnight. The crystals werecollected by filtration and washed with a 9:1 mixed solvent of methanoland water and dried to giveN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide46 (26.35 g, yield 93%) as white crystals.

MS ESI m/e: 652 (M+H), 650 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.72 (m, 2H), 0.91-1.01 (m, 2H), 1.25(s, 3H), 2.57-2.67 (m, 1H), 3.01 (s, 3H), 3.08 (s, 3H), 6.92 (t, J=9.0Hz, 1H), 7.09-7.14 (m, 1H), 7.20-7.26 (m, 2H), 7.37-7.45 (m, 1H),7.52-7.58 (m, 1H), 7.79 (dd, J=1.8, 9.0 Hz, 1H), 9.89 (s, 1H), 11.08 (s,1H).

Example 3-2 to 3-6, 3-8 and 3-9

In the same manner as in Examples 3-1 and 3-7, the compounds of Examples3-2 to 3-6, 3-8 and 3-9 were obtained. The structural formulas thereofare shown in Table 3-1 to 3-2 with Examples 3-1 and 3-7.

TABLE 3-1 Ex. No. structural formula 3-1

3-2

3-3

3-4

3-5

3-6

TABLE 3-2 Ex. No. structural formula 3-7

3-8

3-9

Example 3-10

By treatingN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide46 according to conventional methods, sodium salt and potassium saltthereof were obtained.

N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamidesodium salt

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.47 (brs, 2H), 0.70-0.90 (m, 2H), 1.23 (s,3H), 2.35 (brs, 1H), 2.82 (s, 3H), 3.22 (s, 3H), 6.69 (t, J=8.8 Hz, 1H),6.81 (d, J=8.1 Hz, 1H), 6.98 (s, 1H), 7.02 (d, J=8.8 Hz, 1H), 7.10-7.30(m, 2H), 7.38 (d, J=9.2 Hz, 1H), 10.22 (brs, 1H).

MS (ESI) m/z 652 [MH]⁺.

N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamidepotassium salt Example 4-1N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamideStep 1 Synthesis of 1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl) urea

Under a nitrogen atmosphere, to N,N-carbonyldiimidazole (39.9 g) wereadded N,N-dimethylformamide (200 ml) and triethylamine (34.3 ml) and asolution of 2-fluoro-4-iodoaniline 47 (48.5 g) in N,N-dimethylformamide(50 ml) was added dropwise with stirring under ice-cooling. After thecompletion of the dropwise addition, the mixture was stirred at roomtemperature for 18 hrs. The reaction mixture was ice-cooled, andcyclopropylamine (21.3 ml) was added dropwise. The reaction mixture wasstirred at room temperature for 1 hr and added dropwise to water-toluene[2:1 (volume ratio), 750 ml] with stirring. The precipitated crystalswere collected by filtration and dried to give1-cyclopropyl-3-(2-fluoro-4-iodophenyl)urea 48 (61.3 g, yield 93.4%) ascolorless crystals.

Step 2 Synthesis of1-cyclopropyl-3-(2-fluoro-4-iodophenyl)pyrimidine-2,4,6-trione

To 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)urea 48 (61.0 g) obtained inStep 1 and malonic acid 4 (19.9 g) were added acetic anhydride (300 ml)and acetyl chloride (27.2 ml), and the mixture was stirred under anitrogen atmosphere at 60° C. for 3 hrs. After allowing to cool to roomtemperature, the reaction mixture was added dropwise to water-toluene[2:1 (volume ratio), 900 ml] with stirring. The precipitated crystalswere collected by filtration and dried to give1-cyclopropyl-3-(2-fluoro-4-iodophenyl)pyrimidine-2,4,6-trione 49 (60.9g, yield 82%) as pale-yellow crystals.

Step 3 Synthesis of6-chloro-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione

To 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-pyrimidine-2,4,6-trione 49(59.0 g) obtained in Step 2 were added phosphorus oxychloride (85.0 ml)and dimethylaniline (29.0 ml), and water (8.3 ml) was added dropwise tothe mixture at room temperature with stirring. After the completion ofthe dropwise addition, the mixture was stirred with heating at 110° C.for 1 hr. After allowing to cool to room temperature, the reactionmixture was added dropwise to ice water-toluene [2:1 (volume ratio), 900ml] with stirring. The mixture was stirred at room temperature for 1 hr.The organic layer was separated, and washed successively with water (300ml) and brine (300 ml). Anhydrous magnesium sulfate and activated carbonwere added and the mixture was stirred. Anhydrous magnesium sulfate andactivated carbon were filtered off, and the filtrate was concentratedunder reduced pressure to give a 1:2 mixture (62.9 g) of6-chloro-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione50 and6-chloro-1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione51 as a yellow foamy oil, which was used for the next step withoutpurification.

Step 4 Synthesis of3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,4-dione

To a 1:2 mixture (62.9 g) of6-chloro-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione50 and6-chloro-1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione51 obtained in Step 3 were added methanol (189 ml) and a solution (126ml) of 40% methylamine in methanol, and the mixture was stirred at roomtemperature for 2 hrs. The precipitated crystals were filtered off andthe filtrate was concentrated under reduced pressure. The residue wasextracted with chloroform (200 ml) and water (200 ml), and the organiclayer was washed with brine (200 ml) and dried over anhydrous magnesiumsulfate. Anhydrous magnesium sulfate was filtered off and the filtratewas concentrated under reduced pressure to give a 2:1 mixture (34.55 g)of3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,4-dione52 and1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,4,-dione53 as yellow crystals, which were used for the next step withoutpurification.

Step 5 Synthesis of3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione

To a 2:1 mixture (34.6 g) of3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,4-dione52 and1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)6-methylamino-1H-pyrimidine-2,4,-dione53 obtained in Step 4, and 2-methylmalonic acid 54 (10.2 g) was addedacetic anhydride (173 ml), and the mixture was stirred at 100° C. for 2hrs. After allowing to cool to room temperature, the reaction mixturewas concentrated under reduced pressure. Acetone (104 ml) was added tothe residue, and the mixture was stirred with heating under reflux for30 min. After allowing to cool to room temperature, the precipitatedcrystals were collected by filtration and dried to give3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione55 (15.1 g, yield from 48, 21%) as colorless crystals.

Step 6 Synthesis of trifluoromethanesulfonic acid3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester

Under a nitrogen atmosphere, to3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethyl-1H,H-pyrido[2,3-d]pyrimidine-2,4,7-trione 55 (33.0 g) obtained in Step 5were added chloroform (165 ml) and 2,6-lutidine (10.4 ml), andtrifluoromethanesulfonic anhydride 56 (14.4 ml) was added dropwise underice-cooling with stirring. After the completion of the dropwiseaddition, the mixture was stirred at same temperature for 30 min and atroom temperature for 2 hrs. The reaction mixture was washed successivelywith aqueous sodium hydrogen carbonate (165 ml), 1N hydrochloric acid(165 ml) and brine (165 ml) and dried over anhydrous magnesium sulfate.Anhydrous magnesium sulfate was filtered off and the filtrate wasconcentrated under reduced pressure. 2-Propanol (198 ml) was added tothe residue, and the mixture was stirred with heating under reflux, andallowed to return to room temperature. The crystals were collected byfiltration and dried to give trifluoromethanesulfonic acid3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester 43 (31.9 g, yield 93%) as colorless crystals.

Step 7 Synthesis ofN-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}acetamide

To trifluoromethanesulfonic acid3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester 43 (25.0 g) obtained in Step 6 and 3′-aminoacetanilide 57 (7.33 g)were added N,N-dimethylacetamide (50.0 ml) and 2,6-lutidine (5.68 ml),and the mixture was stirred at 130° C. for 5 hrs. After allowing to coolto room temperature, methanol-water [1:2 (volume ratio), 150 ml] wasadded with stirring. The crystals were collected by filtration and driedto giveN-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}acetamide58 (24.8 g, yield 99%) as colorless crystals.

Step 8 Synthesis ofN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide

Under a nitrogen atmosphere, to a solution (1.57 g) of 28% sodiummethoxide in methanol was added tetrahydrofuran (40 ml),N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}acetamide58 (5.00 g) obtained in Step 7 was added, and the mixture was stirred atroom temperature for 4 hrs. Acetic acid (0.56 ml) was added, and themixture was stirred at room temperature for 30 min. Water (40 ml) wasadded and the mixture was further stirred for 1 hr. The crystals werecollected by filtration and dried to giveN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide59 (4.75 g, yield 95%) as colorless crystals.

MS ESI m/e: 616 (M+H), 614 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.63-0.70 (m, 2H), 0.91-1.00 (m, 2H), 1.25(s, 3H), 2.04 (s, 3H), 2.58-2.66 (m, 1H), 3.07 (s, 3H), 6.92 (t, J=8.8Hz, 1H), 7.00-7.05 (m, 1H), 7.36 (t, J=8.2 Hz, 1H), 7.52-7.63 (m, 3H),7.79 (dd, J=2.0, 10.4 Hz, 1H), 10.10 (s, 1H), 11.08 (s, 1H).

Example 4-1 Alternative MethodN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamideStep 1 Synthesis of 1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea

Under a nitrogen atmosphere, to N,N-carbonyldiimidazole (82.1 g) wereadded N,N-dimethylformamide (400 ml) and triethylamine (70.5 ml), and asolution of 2-fluoro-4-iodoaniline 47 (100 g) in N,N-dimethylformamide(100 ml) was added dropwise under ice-cooling. After the completion ofthe dropwise addition, the mixture was stirred at room temperature for 5hrs. The reaction mixture was ice-cooled, and cyclopropylamine (44.0 ml)was added dropwise. The mixture was stirred at room temperature for 1hr, and the reaction mixture was added dropwise to water-toluene [2:1(volume ratio), 1500 ml] with stirring. The precipitated crystals werecollected by filtration and dried to give1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 48 (129 g, yield 95.5%) ascolorless crystals.

Step 2 Synthesis of1-(2-cyano-acetyl)-1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea

Under a nitrogen atmosphere, to1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 48 (167 g) and cyanoaceticacid 73 (80.0 g), was added N,N-dimethylformamide (836 ml), andmethanesulfonyl chloride (72.8 ml) was added dropwise with stirring atroom temperature. The mixture was stirred at room temperature for 4 hrs.The reaction mixture was cooled with water, and water-isopropanol [2:1(volume ratio), 1670 ml] was added dropwise. The mixture was stirredunder water-cooling for 1 hr, and the precipitated crystals werecollected by filtration and dried to give1-(2-cyano-acetyl)-1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 74 (192g).

Step 3 Synthesis of6-amino-3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-1H-pyrimidine-2,4-dione

To 1-(2-cyano-acetyl)-1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 74(192 g) were added water (962 ml) and 2N aqueous sodium hydroxidesolution (24.9 ml), and the mixture was stirred with heating at 80° C.for 1 hr. After allowing to cool to room temperature, the crystals werecollected by filtration and dried to give6-amino-3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-1H-pyrimidine-2,4-dione75 (178 g, yield from 48, 88%) as pale-yellow crystals.

Step 4 Synthesis ofN′-[1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine

Under a nitrogen atmosphere, to6-amino-3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-1H-pyrimidine-2,4-dione75 (178 g) were added N,N-dimethylformamide (356 ml) andN,N-dimethylformamide dimethylacetal (178 ml), and the mixture wasstirred at room temperature for 2 hrs. Isopropanol (178 ml) was addedwith stirring at room temperature, and water (1068 ml) was addeddropwise. The mixture was stirred at room temperature for 2 hrs, and theprecipitated crystals were collected by filtration and dried to giveN′-[1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine76 (188 g, yield 92%) as yellow crystals.

Step 5 Synthesis of3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6-methylamino-1H-pyrimidine-2,4-dione

Under a nitrogen atmosphere, to t-butanol-ethanol [2:1 (volume ratio),250 ml] was added sodium borohydride (6.41 g), and the mixture wasstirred at room temperature for 1 hr. Under water-cooling,N′-[1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine76 (50.0 g) was added, and the mixture was stirred for 2.5 hrs. Underwater-cooling, water (225 ml) and 10% aqueous citric acid solution (175ml) were successively added dropwise, and the mixture was stirred for 3hrs. The precipitated crystals were collected by filtration and dried togive crude crystals (34.5 g, LC purity 91%) of3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6-methylamino-1H-pyrimidine-2,4-dione52, which were used for the next reaction without purification.

Step 6 Synthesis of3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione

Under a nitrogen atmosphere, to3-cyclopropy-1-(2-fluoro-4-iodo-phenyl)-6-methylamino-1H-pyrimidine-2,4-dione52 (34.4 g) and 2-methyl-malonic acid 54 (15.2 g) was added aceticanhydride (34.4 ml), and the mixture was stirred with heating at 100° C.for 3 hrs. After allowing to cool to 50° C., acetone (68.8 ml) was addeddropwise, and the mixture was stirred as it was for 30 min. Water (172ml) was further added dropwise, and the mixture was stirred for 1 hr.After allowing to cool to room temperature with stirring, theprecipitated crystals were collected by filtration and dried to givecrude crystals (37.7 g, LC purity 91%) of3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione55. Isopropanol (92.0 ml) was added to the obtained crude crystals (30.7g), and the mixture was stirred at room temperature for 4 hrs. Thecrystals were collected by filtration and dried to give3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione55 (25.9 g, yield from 76, 58%) as pale-yellow crystals.

Step 7 Synthesis of p-toluenesulfonic acid3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester

Under a nitrogen atmosphere, to3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione55 (23.9 g) was added acetonitrile (167 ml), and the mixture was stirredunder ice-cooling. Triethylamine (11.0 ml) and trimethylaminehydrochloride (2.37 g) were added, and a solution of p-toluenesulfonylchloride 11 (12.3 g) in acetonitrile (72.0 ml) was added dropwise. Themixture was stirred under ice-cooling for 1 hr, and stirred at roomtemperature for 3 hrs. Methanol (239 ml) was added, and the mixture wasstirred at room temperature for 1 hr. The crystals were collected byfiltration and dried to give p-toluenesulfonic acid3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester 77 (28.7 g, yield 91%) as colorless crystals.

Step 8 Synthesis ofN-{3-[3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide

To p-toluenesulfonic acid3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester 77 (28.0 g) and 3′-aminoacetanilide 57 (13.2 g) were addedN,N-dimethylacetamide (84.0 ml) and 2,6-lutidine (15.3 ml), and themixture was stirred at 130° C. for 4 hrs. After allowing to cool withstirring, methanol (196 ml) was added dropwise, and the mixture wasstirred at room temperature. The crystals were collected by filtrationand dried to giveN-{3-[3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide58 (25.2 g, yield 93%) as colorless crystals.

Step 9 Synthesis ofN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide

Under a nitrogen atmosphere, toN-{3-[3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide58 (45.7 g) was added tetrahydrofuran (366 ml), and a solution (15.7 g)of 28% sodium methoxide in methanol was added dropwise with stirring atroom temperature and the mixture was stirred at room temperature for 4hrs. Acetic acid (5.61 ml) was added, and the mixture was stirred atroom temperature for 30 min. With stirring at 70° C. in an oil bath,water (366 ml) was added dropwise, and the mixture was stirred for 1 hr.After allowing to cool with stirring, the crystals were collected byfiltration and dried to give crystal 1 (46.0 g) ofN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide59.

N,N-Dimethylacetamide (184 ml) was added to crystal 1 (46.0 g), and themixture was stirred with heating at 130° C. After complete dissolution,the solution was filtered by suction using with paper (5B), and washedwith N,N-dimethylacetamide (92.0 ml). The filtrate was stirred underheating at 130° C., 1-butanol (138 ml) and water (96.0 ml) weresuccessively added dropwise, and the mixture was stirred for 30 min.Water (46.0 ml) was further added dropwise, and the mixture was stirredfor 30 min allowed to cool with stirring. The crystals were collected byfiltration and dried to give crystal 2 (41.7 g) ofN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide59 as colorless crystals.

To crystal 2 (41.5 g) was added 1-butanol-water [19:1 (volume ratio),415 ml], and the mixture was stirred at 130° C. for 18 hrs. Afterallowing to cool with stirring, the crystals 25 were collected byfiltration and dried to giveN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide 59 (40.7 g, yield 89%) ascolorless crystals.

Example 4-3N-{3-[3-cyclopropyl-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamideStep 1 Synthesis ofN-{3-[3-cyclopropyl-5-(2-fluoro-4-trimethylsilanylethynylphenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide

Under a nitrogen atmosphere, toN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide59 (14.5 g) obtained in Example 4-1 were added chloroform (145 ml),trimethylsilylacetylene 60 (4.99 ml) and triethylamine (13.1 ml).Copper(I) iodide (22 mg) andbis(triphenylphosphine)palladium(II)chloride (83 mg) were added, and themixture was stirred at room temperature for 20 hrs. The mixture wasconcentrated under reduced pressure, activated carbon (435 mg) andmethanol (435 ml) were added to the residue, and the mixture was stirredwith heating at reflux for 2 hrs. Activated carbon was filtered offwhile it was hot, and the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography(chloroform:acetone=10:1→4:1) and toluene-acetone [5:1 (volume ratio),87 ml] was added to the obtained crystals. The mixture was stirred at80° C. for 1 hr. After allowing to cool to room temperature, thecrystals were collected by filtration and dried to giveN-{3-[3-cyclopropyl-5-(2-fluoro-4-trimethylsilanylethynylphenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide61 (12.9 g, yield 93%) as pale-yellow crystals.

Step 2 Synthesis ofN-{3-[3-cyclopropyl-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide

ToN-{3-[3-cyclopropyl-5-(2-fluoro-4-trimethylsilanylethynylphenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide61 (1.00 g) obtained in Step 2 and potassium carbonate (236 mg) wasadded methanol/N,N-dimethylformamide [1:1 (volume ratio), 10.0 ml], andthe mixture was stirred at room temperature for 20 hrs. The mixture wasneutralized with 2N hydrochloric acid, water (10.0 ml) was added, andthe mixture was stirred at room temperature for 1 hr. The crystals werecollected by filtration and dried to giveN-{3-[3-cyclopropyl-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide62 (815 mg, yield 93%) as pale-yellow crystals.

MS ESI m/e: 514 (M+H), 512 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.63-0.70 (m, 2H), 0.91-0.99 (m, 2H), 1.26(s, 3H), 2.04 (s, 3H), 2.58-2.66 (m, 1H), 3.10 (s, 3H), 4.30 (s, 3H),7.01-7.06 (m, 1H), 7.09 (t, J=8.4 Hz, 1H), 7.31 (dd, J=1.6, 8.4 Hz, 1H),7.36 (t, J=7.8 Hz, 1H), 7.52 (dd, J=1.6, 11.6 Hz, 1H), 7.57-7.63 (m,2H), 10.10 (s, 1H), 11.10 (s, 1H).

Example 4-16N-{3-[5-(2-fluoro-4-iodophenylamino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamideStep 1 Synthesis of 1-(2-fluoro-4-iodophenyl)-3-methylurea

Under a nitrogen atmosphere, to N,N-carbonyldiimidazole (61.4 g) wereadded N,N-dimethylformamide (300 ml) and triethylamine (52.8 ml) and asolution of 2-fluoro-4-iodoaniline 47 (74.8 g) in N,N-dimethylformamide(75 ml) was added dropwise with stirring under ice-cooling. After thecompletion of the dropwise addition, the mixture was stirred at roomtemperature for 5 hrs. The reaction mixture was ice-cooled, and asolution (60 ml) of 40% methylamine in methanol was added dropwise. Themixture was stirred at room temperature for 1 hr, and the reactionmixture was added dropwise to water-toluene [2:1 (volume ratio), 1125ml] under stirring. The precipitated crystals were collected byfiltration and dried to give 1-(2-fluoro-4-iodophenyl)-3-methylurea 63(87.9 g, yield 94.8%) as colorless crystals.

Step 2 Synthesis of1-(2-fluoro-4-iodophenyl)-3-methylpyrimidine-2,4,6-trione

Under a nitrogen atmosphere, to 1-(2-fluoro-4-iodophenyl)-3-methylurea63 (87.9 g) obtained in Step 1 and malonic acid 4 (31.1 g) were addedacetic anhydride (264 ml) and acetyl chloride (42.5 ml), and the mixturewas stirred at 65° C. for 3 hrs. After allowing to cool to roomtemperature, the reaction mixture was added dropwise to water-toluene[2:1 (volume ratio), 800 ml] with stirring, and hexane (132 ml) wassuccessively added. The precipitated crystals were collected byfiltration and dried to give1-(2-fluoro-4-iodophenyl)-3-methylpyrimidine-2,4,6-trione 64 (75.3 g,yield 69.5%) as pale-yellow crystals.

Step 3 Synthesis of6-chloro-1-(2-fluoro-4-iodophenyl)-3-methyl-1H-pyrimidine-2,4-dione

Under a nitrogen atmosphere, to1-(2-fluoro-4-iodophenyl)-3-methylpyrimidine-2,4,6-trione 64 (75.3 g)were added phosphorus oxychloride (116.3 ml) and dimethylaniline (39.5ml) and water (11.6 ml) was added dropwise with stirring under roomtemperature. After the completion of the dropwise addition, the mixturewas stirred at 125° C. for 1 hr. After allowing to cool to roomtemperature, the reaction mixture was added dropwise with stirring toice water (500 ml)/chloroform (150 ml). The mixture was stirred at roomtemperature for 1 hr, and chloroform (150 ml) was added. The organiclayer was separated, washed successively with water (300 ml) and brine(300 ml), and dried over anhydrous sodium sulfate.

Anhydrous sodium sulfate was filtered off, and the filtrate wasconcentrated under reduced pressure. To a solution of the residue inchloroform (250 ml), silica gel (200 ml) was added and the mixture wasstirred. Silica gel was to filtered off and washed with chloroform/ethylacetate [10:1 (volume ratio), 11]. The filtrate was concentrated underreduced pressure to give a 6:5 mixture (75.7 g, yield 95.6%) of6-chloro-1-(2-fluoro-4-iodophenyl)-3-methyl-1H-pyrimidine-2,4-dione 65and 6-chloro-3-(2-fluoro-4-iodophenyl)-1-methyl-1H-pyrimidine-2,4-dione66 as pale-yellow crystals.

Step 4 Synthesis of1-(2-fluoro-4-iodophenyl)-3-methyl-6-methylamino-1H-pyrimidine-2,4-dione

To a 6:5 mixture (75.7 g) of6-chloro-1-(2-fluoro-4-iodophenyl)-3-methyl-1H-pyrimidine-2,4-dione 65and 6-chloro-3-(2-fluoro-4-iodophenyl)-1-methyl-1H-pyrimidine-2,4-dione66 obtained in Step 3 were added methanol (227 ml) and 40% solution (152ml) of methylamine in methanol, and the mixture was stirred at roomtemperature for 2.5 hrs. The reaction mixture was concentrated underreduced pressure, and toluene (150 ml) and water (150 ml) were added tothe residue, and the mixture was stirred under heating at reflux for 30min. After allowing to return to room temperature, the crystals werecollected by filtration and dried to give a 6:5 mixture (59.6 g, yield79.9%) of1-(2-fluoro-4-iodophenyl)-3-methyl-6-methylamino-1H-pyrimidine-2,4-dione67 and3-(2-fluoro-4-iodophenyl)-1-methyl-6-methylamino-1H-pyrimidine-2,4-dione68 as pale-yellow crystals.

Step 5 Synthesis of1-(2-fluoro-4-iodophenyl)-5-hydroxy-3,6,8-trimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione

To a 6:5 mixture (59.6 g) of1-(2-fluoro-4-iodophenyl)-3-methyl-6-methylamino-1H-pyrimidine-2,4-dione67 and3-(2-fluoro-4-iodophenyl)-1-methyl-6-methylamino-1H-pyrimidine-2,4-dione68 obtained in Step 4 and 2-methyl-malonic acid 54 (20.7 g) was addedacetic anhydride (180 ml), and the mixture was stirred with heating at95° C. for 1 hr. After allowing to cool to room temperature, the mixturewas concentrated under reduced pressure. Tetrahydrofuran (350 ml) wasadded to the residue, and the mixture was stirred with heating underreflux for 1 hr. After allowing to cool to room temperature, thecrystals were filtered off. The filtrate was concentrated under reducedpressure and the residue was purified by column chromatography(chloroform:tetrahydrofuran=18:1). Toluene (150 ml) was added to theobtained solid, and the mixture was stirred with heating under refluxfor 30 min. After allowing to return to room temperature, the crystalswere collected by filtration and dried to give1-(2-fluoro-4-iodophenyl)-5-hydroxy-3,6,8-trimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione69 (27.0 g, yield 37%) as colorless crystals.

Step 6 Synthesis of trifluoromethanesulfonic acid1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester

Under a nitrogen atmosphere, to1-(2-fluoro-4-iodophenyl)-5-hydroxy-3,6,8-trimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione69 (27.0 g) obtained in Step 5 were added chloroform (200 ml) and2,6-lutidine (11.1 ml) and trifluoromethanesulfonic anhydride 56 (14.9ml) was added dropwise under ice-cooling with stirring. After thecompletion of the dropwise addition, the mixture was stirred at the sametemperature for 30 min, and at room temperature for 3 hrs. With stirringunder ice-cooling, water (200 ml) was added to the reaction mixture. Theorganic layer was separated, washed successively with water (300 ml) andbrine (300 ml), and dried over anhydrous magnesium sulfate. Anhydrousmagnesium sulfate was filtered off, and the filtrate was concentratedunder reduced pressure. 2-Propanol (150 ml) was added to the residue,and seed crystals were added at room temperature to allow precipitationof the crystals. The mixture was stirred with heating under reflux for30 min, and allowed to cool to room temperature. The crystals werecollected by filtration and dried to give trifluoromethanesulfonic acid1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester 70 (22.9 g, yield 66%) as colorless crystals.

Step 7 Synthesis ofN-{3-[1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide

To trifluoromethanesulfonic acid1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylester 70 (3.00 g) obtained in Step 6 andN-(3-aminophenyl)methanesulfonamide 44 (1.14 g) were addedN,N-dimethylacetamide (6.00 ml) and 2,6-lutidine (0.712 ml), and themixture was stirred at 130° C. for 4 hrs. After allowing to cool to roomtemperature, methanol/water [1:2 (volume ratio), 18.0 ml] was addedunder stirring. The crystals were collected by filtration and dried togiveN-{3-[1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide71 (3.13 g, yield 98%) as a pale-gray solid.

Step 8 Synthesis ofN-{3-[5-(2-fluoro-4-iodophenylamino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide

Under ice-cooling, to a suspension ofN-{3-[1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide71 (3.10 g) obtained in Step 7 in tetrahydrofuran (31.0 ml) was addeddropwise a mixture of potassium t-butoxide (1.33 g), methanol (0.482 ml)and tetrahydrofuran (15.5 ml), and the mixture was stirred underice-cooling for 2 hrs. Acetic acid (1.36 ml) was added, the mixture wasallowed to warm to room temperature and stirred for 1 hr. The reactionmixture was concentrated, methanol/water [1:2 (volume ratio), 45.0 ml]was added, and the mixture was further stirred at room temperature for 1hr. The crystals were collected by filtration and dried to giveN-{3-[5-(2-fluoro-4-iodophenylamino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide72 (3.01 g, yield 97%) as a pale-gray solid.

MS ESI m/e: 626 (M+H), 624 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.26 (s, 3H), 3.01 (s, 3H), 3.09 (s, 3H),3.21 (s, 3H), 6.93 (t, J=8.3 Hz, 1H), 7.11-7.15 (m, 1H), 7.20-7.28 (m,2H), 7.42 (t, J=8.3 Hz, 1H), 7.52-7.57 (m, 1H), 7.76-7.81 (m, 1H), 9.94(brs, 1H), 11.21 (brs, 1H).

Example 4-144N-{3-[5-(2-Fluoro-4-iodophenylamino)-3-(4-hydroxybutyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamideStep 1 Synthesis of (2-fluoro-4-iodophenyl)-urea

Under argon atmosphere, to a solution of 2-fluoro-4-iodoaniline 47 (20.0g) and triethylamine (23.6 ml) in chloroform (200 ml) was addedN,N-carbonyldiimidazole (27.4 g) with stirring under ice-cooling. Afterthe completion of the addition, the mixture was stirred underice-cooling for 15 min and at room temperature for 4 hrs. The reactionmixture was ice-cooled, and 28% aqueous ammonia (100 ml) was addeddropwise. The mixture was stirred at room temperature for 1.5 hrs. Theprecipitated crystals were collected by filtration, washed with waterand dried to give (2-fluoro-4-iodophenyl)-urea 78 (23.5 g, yield 98.8%)as pale-pink crystals.

Step 2 Synthesis of 1-(2-cyanoacetyl)-3-(2-fluoro-4-iodophenyl)-urea

To a mixture of (2-fluoro-4-iodophenyl)-urea 78 (21.7 g) and cyanoaceticacid 73 (7.88 g) in N,N-dimethylformamide (108 ml) was added, andmethanesulfonyl chloride (7.17 ml) was added dropwise with stirring atroom temperature. The mixture was stirred at room temperature for 2 hrs,and water-isopropyl alcohol [1:2 (volume ratio), 210 ml] was addeddropwise. The mixture was stirred at room temperature for 1 hr. Theprecipitated crystals were collected by filtration and washed with waterto give 1-(2-cyanoacetyl)-3-(2-fluoro-4-iodophenyl)-urea 79 (wetcrystals), which was used for the next reaction in the form of wetcrystals.

Step 3 Synthesis of6-amino-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione

To a suspension of 1-(2-cyanoacetyl)-3-(2-fluoro-4-iodophenyl)-urea 79(wet crystals) in water (110 ml) was added 2N aqueous sodium hydroxidesolution (3.96 ml), and the mixture was stirred with heating at 85° C.for 1 hr. After allowing to cool to room temperature, 2N hydrochloricacid (3.96 ml) and isopropyl alcohol (44.0 ml) were successively addeddropwise. The mixture was stirred at room temperature for 1.5 hrs, theprecipitated crystals were collected by filtration, washed withisopropyl alcohol, and dried to give a mixture of6-amino-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 80 and 78(21.8 g) as colorless crystals, which were used for the next reactionwithout purification.

Step 4 Synthesis ofN′-[3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformamidine

To a mixture (21.8 g) of6-amino-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 80 and 78 wasadded N,N-dimethylformamide (42.0 ml) andN,N-dimethylformamidedimethylacetal (21.0 ml) and the mixture wasstirred at room temperature for 4.5 hrs. With stirring at roomtemperature, isopropyl alcohol (20.0 ml) was added, and water (100 ml)was added dropwise. The mixture was stirred at room temperature for 45min, and the precipitated crystals were collected by filtration, washedwith water and dried to giveN′-[3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformamidine81 (21.7 g, yield 67.7% from 78) as colorless crystals.

Step 5 Synthesis ofN′-[3-(2-fluoro-4-iodophenyl)-1-(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformamidine

To a solution ofN′-[3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformamidine81 (20.0 g) in N,N-dimethylformamide (150 ml) was added1,8-diazabicyclo[5.4.0]undec-7-en (14.9 ml) and 4-methoxybenzyl chloride82 (10.1 ml) at room temperature. The mixture was stirred with heatingat 75° C. for 2.5 hrs, 1,8-diazabicyclo[5.4.0]undec-7-en (7.50 ml) and4-methoxybenzyl chloride (4.00 ml) were added, and the mixture wasstirred with heating at the same temperature for 2.5 hrs. After allowingto cool to room temperature, isopropyl alcohol (150 ml) and water (300ml) were successively added dropwise. The mixture was stirred overnightat room temperature, and the precipitated crystals were collected byfiltration and dried to giveN′-[3-(2-fluoro-4-iodophenyl)-1-(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformamidine83 (20.2 g, yield 77.8%) as yellow crystals.

Step 6 Synthesis of1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6-methylamino-1H-pyrimidine-2,4-dione

To a suspension of sodium borohydride (326 mg) in t-butanol/ethanol [2:1(volume ratio), 18.0 ml] was addedN′-[3-(2-fluoro-4-iodophenyl)-1-(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformamidine83 (3.00 g) with stirring at room temperature. The mixture was stirredat room temperature for 1 hr, and at 65° C. for 2 hrs. With stirring atthe same temperature, water (30.0 ml) and ammonium chloride (461 mg)were successively added, and the mixture was stirred to allow to cool toroom temperature. The reaction solution was extracted twice with ethylacetate. The organic layers were combined, washed successively withsaturated aqueous hydrogen carbonate solution and brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained crude product was purified by column chromatography to give1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6-methylamino-H-pyrimidine-2,4-dione84 (2.57 g, yield 93.1%) as a pale-yellow solid.

Step 7 Synthesis of1-(2-fluoro-4-iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione

To a suspension of1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6-methylamino-1H-pyrimidine-2,4-dione84 (13.3 g) in acetic anhydride (13.0 ml) was added 2-methyl-malonicacid 54 (4.90 g), and the mixture was stirred with heating at 90° C. for3 hrs and at 100° C. for 1 hr. After allowing to cool to about 50° C.,acetone (13.3 ml) was added dropwise, and water (75.0 ml) was furtheradded. After seeding with compound 85, acetone (30.0 ml) was added, andthe mixture was stirred for 1.5 hrs. Water (30.0 ml) as added and themixture was stirred for 45 min, and allowed to cool to room temperature.The precipitated crystals were collected by filtration, washed withwater and dried to give1-(2-fluoro-4-iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione85 (14.1 g, yield 90.7%) as pale-ocher crystals.

Step 8 Synthesis of trifluoromethanesulfonic acid1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylester

Under argon atmosphere, to a solution of1-(2-fluoro-4-iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione85 (14.1 g) in chloroform (70.0 ml) was added 2,6-lutidine (3.79 ml) andtrifluoromethanesulfonic anhydride 56 (5.47 ml) under ice-cooling, andthe mixture was stirred under ice-cooling for 1 hr, and at roomtemperature for 1.5 hrs. To the reaction mixture was added saturatedaqueous sodium hydrogen carbonate solution and chloroform to allowpartitioning. The organic layer was washed once with saturated aqueoussodium hydrogen carbonate solution, twice with 1N hydrochloric acid,once with saturated aqueous sodium chloride solution, and dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. To the obtained crude product wasadded isopropyl alcohol (35.0 ml), and the mixture was stirred withheating at an outer temperature of 95° C. for 30 min. After allowing tocool with stirring to room temperature, isopropyl alcohol (35.0 ml) wasadded, and the mixture was stirred for 1 hr. The precipitated crystalswere collected by filtration, washed with isopropyl alcohol and dried togive trifluoromethanesulfonic acid1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylester 86 (14.4 g, yield 82.8%) as brown crystals.

Step 9 Synthesis ofN-{3-[1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide

To trifluoromethanesulfonic acid1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylester 86 (1.10 g) and 3′-aminoacetanilide 57 (285 mg) were added,N,N-dimethylacetamide (2.20 ml) and 2,6-lutidine (221 μl), and themixture was stirred at 130° C. for 2 hrs. After allowing to return toroom temperature, methanol (12.0 ml) was added dropwise with stirring.The precipitated crystals were collected by filtration, washed withmethanol and dried to giveN-{3-[1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide87 (1.04 g, yield 94.6%) as colorless crystals.

Step 10 Synthesis ofN-{3-[5-(2-fluoro-4-iodophenylamino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide

To a solution (305 mg) of 28% sodium methoxide in methanol were addedtetrahydrofuran (4.00 ml) andN-{3-[1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide87 (1.00 g). The wall was washed with tetrahydrofuran (4.00 ml). Themixture was stirred at room temperature for 1.5 hrs., 2N hydrochloricacid (900 μl) was added, and the mixture was concentrated under reducedpressure. To the residue was added isopropyl alcohol, methanol andwater, and after refluxing, the mixture was allowed to cool to roomtemperature with stirring. The precipitated crystals were collected byfiltration, washed with methanol, and dried to giveN-{3-[5-(2-fluoro-4-iodophenylamino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide88 (974 mg, yield 97.2%) as colorless crystals.

Step 11 Synthesis ofN-{3-[5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide

To a suspension ofN-{3-[5-(2-fluoro-4-iodophenylamino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide88 (960 mg) in anisole (10.0 ml) was added aluminum chloride (1.94 g)with stirring in a water bath. The mixture was stirred at roomtemperature for 37 hrs, methanol (12.0 ml) was added dropwise, and themixture was concentrated under reduced pressure. The obtained residuewas dissolved in methanol (12.0 ml), and 2N hydrochloric acid (20.0 ml)was added dropwise with stirring in a water bath. The mixture wasstirred at room temperature for 1 hr, hexane (10.0 ml) was added, andthe mixture was stirred for 1 hr. The precipitated crystals werecollected by filtration, washed with hexane, water and methanol, anddried to giveN-{3-[5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide89 (620 mg, yield 78.1%) as colorless crystals.

Step 12 Synthesis ofN-{3-[3-(4-benzyloxybutyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide

Under argon atmosphere, to a suspension ofN-{3-[5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide89 (75.0 mg), 4-benzyloxybutyl alcohol 90 (25.0 μl) andtriphenylphosphine (37.0 mg) in tetrahydrofuran (1.00 ml) was addeddiisopropyl azodicarboxylate (28.0 μl) with stirring under ice cooling.The mixture was stirred at the same temperature for 2 hrs, and4-benzyloxybutyl alcohol (13.0 μl), triphenylphosphine (19.0 mg) anddiisopropyl azodicarboxylate (14.0 μl) were added. The mixture wasstirred at the same temperature for 1 hr, and water and ethyl acetatewere added to allow partitioning. The organic layer was washed withsaturated aqueous sodium chloride solution, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography (chloroform:ethyl acetate=2:1→1:1) andthin layer chromatography (hexane:acetone=1:1) for further purificationto giveN-{3-[3-(4-benzyloxybutyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide91 (74 mg, yield 77%) as a pale-yellow amorphous form.

Step 13 Synthesis ofN-{3-[5-(2-fluoro-4-iodophenylamino)-3-(4-hydroxybutyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide

N-{3-[3-(4-Benzyloxybutyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide91 (74 mg) was stirred under reflux for 5.5 hrs in trifluoroacetic acid(1.00 ml). The reaction mixture was concentrated under reduced pressure,and ethyl acetate and saturated aqueous sodium hydrogen carbonatesolution were added to the residue to allow partitioning. The organiclayer was washed successively with saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure. To the residue was addeddiisopropyl ether (1.00 ml), and the mixture was stirred at 60° C. toallow cooling to room temperature with stirring. The crystals werecollected by filtration, washed with diisopropyl ether, and dried togive compound 93 (26 mg) as colorless crystals. Compound 93 was stirredin a mixed solution of saturated aqueous sodium hydrogen carbonatesolution (300 μl), methanol (300 μl) and ethyl acetate (300 μl) at roomtemperature for 1 hr, and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. To the residue were added ethylacetate, hexane and diethyl ether, and the mixture was stirred at roomtemperature for 1 hr. The precipitated crystals were collected byfiltration, washed with hexane and dried to giveN-{3-[5-(2-fluoro-4-iodophenylamino)-3-(4-hydroxybutyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide92 (5 mg, yield 8%) as colorless crystals.

Examples 4-2, 4-4-15, 4-17-143 and 4-145-148

In the same manner as in Examples 4-1, 4-3 and 4-16, the compounds ofExamples 4-2, 4-4-15, 4-17-133 and 4-138-4-140 were obtained. Inaddition, in the same manner as in Example 4-144, the compounds ofExamples 4-83-86, Examples 4-134-137, 4-141-143 and 4-145-148 wereobtained. The structural formulas thereof are shown in Table 4-1 to 4-25with Examples 4-1, 4-3, 4-16 and 4-144.

TABLE 4-1 Ex. No. structural formula 4-1

4-2

4-3

4-4

4-5

4-6

TABLE 4-2 Ex. No. structural formula 4-7

4-8

4-9

4-10

4-11

4-12

TABLE 4-3 Ex. No. structural formula 4-13

4-14

4-15

4-16

4-17

4-18

TABLE 4-4 Ex. No. structural formula 4-19

4-20

4-21

4-22

4-23

4-24

TABLE 4-5 Ex. No. structural formula 4-25

4-26

4-27

4-28

4-29

4-30

TABLE 4-6 Ex. No. structural formula 4-31

4-32

4-33

4-34

4-35

4-36

TABLE 4-7 Ex. No. structural formula 4-37

4-38

4-39

4-40

4-41

4-42

TABLE 4-8 Ex. No. structural formula 4-43

4-44

4-45

4-46

4-47

4-48

TABLE 4-9 Ex. No. structural formula 4-49

4-50

4-51

4-52

4-53

4-54

TABLE 4-10 Ex. No. structural formula 4-55

4-56

4-57

4-58

4-59

4-60

TABLE 4-11 Ex. No. structural formula 4-61

4-62

4-63

4-64

4-65

4-66

TABLE 4-12 Ex. No. structural formula 4-67

4-68

4-69

4-70

4-71

4-72

TABLE 4-13 Ex. No. structural formula 4-73

4-74

4-75

4-76

4-77

4-78

TABLE 4-14 Ex. No. structural formula 4-79

4-80

4-81

4-82

4-83

4-84

TABLE 4-15 Ex. No. structural formula 4-85

4-86

4-87

4-88

4-89

4-90

TABLE 4-16 Ex. No. structural formula 4-91

4-92

4-93

4-94

4-95

4-96

TABLE 4-17 Ex. No. structural formula 4-97 

4-98 

4-99 

4-100

4-101

4-102

TABLE 4-18 Ex. No. structural formula 4-103

4-104

4-105

4-106

4-107

4-108

TABLE 4-19 Ex. No. structural formula 4-109

4-110

4-111

4-112

4-113

4-114

TABLE 4-20 Ex. No. structural formula 4-115

4-116

4-117

4-118

4-119

4-120

TABLE 4-21 Ex. No. structural formula 4-121

4-122

4-123

4-124

4-125

4-126

TABLE 4-22 Ex. No. structural formula 4-127

4-128

4-129

4-130

4-131

TABLE 4-23 Ex. No. structural formula 4-132

4-133

4-134

4-135

4-136

4-137

TABLE 4-24 Ex. No. structural formula 4-138

4-139

4-140

4-141

4-142

4-143

TABLE 4-25 Ex. No. structural formula 4-144

4-145

4-146

4-147

4-148

Example 4-149

By treatingN-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide59 by a conventional method, sodium salt, hydrate, acetic acid solvate,dimethylsulfoxide solvate, ethanol solvate, nitromethane solvate,chlorobenzene solvate, 1-pentanol solvate, isopropyl alcohol solvate,ethylene glycol solvate and 3-methylbutanol solvate thereof wereobtained.

N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamidesodium salt

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.35-0.41 (m, 2H), 0.71-0.77 (m, 2H), 1.16(s, 3H), 2.02 (s, 3H), 2.18-2.24 (m, 1H), 3.32 (s, 3H), 6.59 (t, J=8.8Hz, 1H), 6.94 (d, J=8.6 Hz, 1H), 7.04 (d, J=10.2 Hz, 1H), 7.19 (d,J=11.1 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 7.34 (s, 1H), 7.64 (d, J=8.3 Hz,1H), 10.00 (s, 1H).

MS (ESI) m/z 616 [MH]⁺.

N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamidehydrate

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.63-0.70 (m, 2H), 0.91-1.00 (m, 2H), 1.25(s, 3H), 2.04 (s, 3H), 2.58-2.66 (m, 1H), 3.08 (s, 3H), 6.92 (t, J=8.8Hz, 1H), 7.00-7.05 (m, 1H), 7.36 (t, J=8.2 Hz, 1H), 7.52-7.63 (m, 3H),7.79 (dd, J=2.0, 10.4 Hz, 1H), 10.09 (s, 1H), 11.08 (s, 1H).

MS (ESI) m/z 616 [MH]⁺.

N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamideacetic acid solvate

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.63-0.70 (m, 2H), 0.92-0.98 (m, 2H), 1.25(s, 3H), 1.91 (s, 3H), 2.04 (s, 3H), 2.59-2.65 (m, 1H), 3.08 (s, 3H),6.92 (t, J=8.6 Hz, 1H), 7.00-7.05 (m, 1H), 7.36 (t, J=7.6 Hz, 1H),7.53-7.62 (m, 3H), 7.79 (dd, J=10.4 Hz, 1H), 10.08 (s, 1H), 11.07 (s,1H), 11.94 (s, 1H).

MS (ESI) m/z 616 [MH]⁺.

N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamidedimethyl sulfoxide solvate

¹H-NMR (CDCl₃, 400 MHz) δ 0.76-0.82 (m, 2H), 1.09-1.15 (m, 2H), 1.41 (s,3H), 2.14 (s, 3H), 2.62 (s, 6H), 2.71-2.77 (m, 1H), 3.20 (s, 3H), 6.70(t, J=8.4 Hz, 1H), 7.00 (brs, 1H), 7.32 (brs, 2H), 7.43-7.47 (m, 1H),7.52 (dd, J=2.0, 9.6 Hz, 1H), 7.71 (brs, 2H), 11.30 (s, 1H).

MS (ESI) m/z 616 [MH]⁴.

N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamideethanol solvate

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.70 (m, 2H), 0.91-1.00 (m, 2H), 1.06(t, J=7.1 Hz, 3H), 1.25 (s, 3H), 2.04 (s, 3H), 2.58-2.66 (m, 1H), 3.07(s, 3H), 3.40-3.49 (m, 2H), 4.33 (t, J 5.1 Hz, 1H), 6.92 (t, J=8.8 Hz,1H), 7.00-7.05 (m, 1H), 7.36 (t, J=8.2 Hz, 1H), 7.52-7.63 (m, 3H), 7.79(dd, J=2.0, 10.4 Hz, 1H), 10.08 (s, 1H), 11.07 (s, 1H).

MS (ESI) m/z 616 [MH]⁺.

N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamidenitromethane solvate

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.70 (m, 2H), 0.91-1.00 (m, 2H), 1.25(s, 3H), 2.04 (s, 3H), 2.58-2.66 (m, 1H), 3.07 (s, 3H), 4.42 (s, 2H),6.92 (t, J=8.8 Hz, 1H), 7.00-7.05 (m, 1H), 7.36 (t, J=8.2 Hz, 1H),7.52-7.63 (m, 3H), 7.79 (dd, J=2.0, 10.4 Hz, 1H), 10.08 (s, 1H), 11.07(s, 1H).

N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamidechlorobenzene solvate

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.70 (m, 2H), 0.91-1.00 (m, 2H), 1.25(s, 3H), 2.04 (s, 3H), 2.58-2.66 (m, 1H), 3.07 (s, 3H), 6.92 (t, J=8.8Hz, 1H), 7.00-7.05 (m, 1H), 7.29-7.45 (m, 5H), 7.50-7.63 (m, 3H), 7.79(dd, J=2.0, 10.4 Hz, 1H), 10.08 (s, 1H), 11.07 (s, 1H).

N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide1-pentanol solvate

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.70 (m, 2H), 0.86 (t, J=7.0 Hz, 1.5H),0.90-0.99 (m, 2H), 1.22-1.30 (m, 5H), 1.35-1.44 (m, 1H), 2.04 (s, 3H),2.56-2.67 (m, 1H), 3.08 (s, 3H), 3.33-3.41 (m, 1H), 4.30 (t, J=5.1 Hz,0.5H), 6.91 (t, J=8.5 Hz, 1H), 7.00-7.06 (m, 1H), 7.36 (t, J=8.3 Hz,1H), 7.52-7.62 (m, 3H), 7.74-7.81 (m, 1H), 10.08 (s, 1H), 11.07 (s, 1H).

N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide isopropyl alcohol solvate

¹H-NMR (DMSO-d, 400 MHz) δ 0.63-0.69 (m, 2H), 0.91-0.98 (m, 2H), 1.04(d, J=6.0 Hz, 6H), 1.25 (s, 3H), 2.04 (s, 3H), 2.58-2.66 (m, 1H), 3.07(s, 3H), 3.73-3.81 (m, 1H), 4.34 (d, J=4.2 Hz, 1H), 6.92 (t, J=8.7 Hz,1H), 7.00-7.05 (m, 1H), 7.36 (t, J=8.3 Hz, 1H), 7.52-7.62 (m, 3H), 7.79(dd, J=1.8, 10.2 Hz, 1H), 10.10 (s, 1H), 11.08 (s, 1H).

N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamideethylene glycol solvate

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.70 (m, 2H), 0.91-1.00 (m, 2H), 1.24(s, 3H), 2.04 (s, 3H), 2.58-2.66 (m, 1H), 3.07 (s, 3H), 3.36-3.41 (m,4H), 4.37-4.44 (m, 2H), 6.92 (t, J=8.8 Hz, 1H), 7.00-7.05 (m, 1H), 7.36(t, J=8.2 Hz, 1H), 7.52-7.63 (m, 3H), 7.79 (dd, J=2.0, 10.4 Hz, 1H),10.10 (s, 1H), 11.08 (s, 1H).

N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide3-methyl-1-butanol solvate

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.64-0.69 (m, 2H), 0.85 (d, J=6.7 Hz, 6H),0.92-0.98 (m, 2H), 1.25 (s, 3H), 1.31 (q, J=6.7 Hz, 2H), 1.60-1.70 (m,1H), 2.04 (s, 3H), 2.59-2.66 (m, 1H), 3.08 (s, 3H), 3.38-3.44 (m, 2H),4.26 (t, J=5.1 Hz, 1H), 6.92 (t, J=8.7 Hz, 1H), 7.01-7.05 (m, 1H), 7.35(t, J=8.0 Hz, 1H), 7.52-7.62 (m, 3H), 7.78 (dd, J=1.9, 10.2 Hz, 1H),10.08 (s, 1H), 11.07 (s, 1H).

Example 4-150

By treatingN-{3-[3-cyclopropyl-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide62 according to a conventional method, acetic acid solvate was obtained.

N-{3-[3-cyclopropyl-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamideacetic acid solvate

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.60-0.70 (m, 2H), 0.90-1.00 (m, 2H), 1.26(s, 3H), 1.91 (s, 3H), 2.04 (s, 3H), 2.59-2.66 (m, 1H), 3.10 (s, 3H),4.29 (s, 1H), 7.01-7.05 (m, 1H), 7.08 (t, J=8.6 Hz, 1H), 7.31 (dd,J=1.6, 8.3 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.52 (dd, J=1.6, 11.3 Hz,1H), 7.57-7.62 (m, 2H), 10.09 (s, 1H), 11.09 (s, 1H), 11.94 (s, 1H).

MS (ESI) m/z 514 [MH]⁺.

Example 4-151

By treatingN-{3-[5-(2-fluoro-4-iodophenylamino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide72 according to a conventional method, a sodium salt was obtained.

N-{3-[5-(2-fluoro-4-iodophenylamino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamidesodium salt

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.25 (s, 3H), 2.78 (s, 3H), 2.97 (s, 3H),3.24 (s, 3H), 6.68 (t, J=8.7 Hz, 1H), 6.77 (d, J=7.5 Hz, 1H), 6.90-7.00(m, 2H), 7.10-7.30 (m, 2H), 7.37 (d, J=10.0 Hz, 1H), 10.30 (brs, 1H).

MS (ESI) m/z 626 [MH]+.

Example 1001-6010

The compounds shown in Tables 11-1 to 11-6 can be obtained in the samemanner as in Examples 1-1 to 1-148 or by other conventional methodemployed as necessary.

TABLE 11-1

Example No. R¹ Example No. R¹ 1001 2-F—Ph— 1002 2-F—Ph— 1003 3-F—Ph—1004 3-F—Ph— 1005 4-F—Ph— 1006 4-F—Ph— 1007 2-Me—Ph— 1008 2-Me—Ph— 10093-Me—Ph— 1010 3-Me—Ph— 1011 4-Me—Ph— 1012 4-Me—Ph— 1013 2-MeO—Ph— 10142-MeO—Ph— 1015 3-MeO—Ph— 1016 3-MeO—Ph— 1017 4-MeO—Ph— 1018 4-MeO—Ph—1019 2-Py— 1020 2-Py— 1021 3-Py— 1022 3-Py— 1023 4-Py— 1024 4-Py— 10252-MeS(CH2)2— 1026 2-MeS(CH2)2— 1027 2-HS(CH2)2— 1028 2-HS(CH2)2— 10294-(Me)2N—Bzl— 1030 4-(Me)2N—Bzl— 1031 3-(Me)2N—Bzl— 1032 3-(Me)2N—Bzl—1033 2-(Me)2N—Bzl— 1034 2-(Me)2N—Bzl— 1035 4-(Me)2N-Phenethyl- 10364-(Me)2N-Phenethyl- 1037 4-HO—Phenethyl- 1038 4-HO—Phenethyl- 10394-HO—Bzl— 1040 4-HO—Bzl— 1041 3-HO—Bzl— 1042 3-HO—Bzl— 1043 2-HO—Bzl—1044 2-HO—Bzl— 1045 4-MeO—Bzl— 1046 4-MeO—Bzl— 1047 4-Py—(CH2)2— 10484-Py—(CH2)2— 1049 3-Py—(CH2)2— 1050 3-Py—(CH2)2— 1051 2-Py—(CH2)2— 10522-Py—(CH2)2— 1053

1054

1055

1056

1057 Allyl- 1058 Allyl- 1059 CF3CH2— 1060 CF3CH2— 1061 n-Propyl- 1062n-Propyl- 1063 Cyclopropylmethyl- 1064 Cyclopropylmethyl- 1065 HO— 1066HO— 1067 HO—(CH2)2—O— 1068 HO—(CH2)2—O— 1069 HO—(CH2)3—O— 1070HO—(CH2)3—O— 1071

1072

1073

1074

1075

1076

1077

1078

1079

1080

1081

1082

1083

1084

Py: Pyridyl, Ph: Phenyl Bzl: Benzyl

TABLE 11-2

Example No. R1 2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

2020

TABLE 11-3

Example No. R³ R⁴ R⁵ 3001 Allyl- Me— H 3002 n-Propyl- Me— H 3003 CF3CH2—Me— H 3004 MeO(CH2)2— Me— H 3005 (Me)2N—(CH2)2— Me— H 3006 Ph— Me— H3007 3-Py Me— H 3008 Me— Allyl- H 3009 Me— MeO— H 3010 Me— Cyclopropyl H3011 Me— Me— HO— 3012 Me— Me— MeO—

TABLE 11-4

Example No. R³ R⁴ R⁵ 4001 Allyl- Me— H 4002 n-Propyl- Me— H 4003 CF3CH2—Me— H 4004 MeO(CH2)2— Me— H 4005 (Me)2N—(CH2)2— Me— H 4006 Ph— Me— H4007 3-Py Me— H 4008 Me— Allyl- H 4009 Me— MeO— H 4010 Me— Cyclopropyl H4011 Me— Me— HO— 4012 Me— Me— MeO—

TABLE 11-5

Example No. R⁶ 5001

5002

5003

5004

5005

5006

5007

5008

5009

5010

TABLE 11-6

Example No. R⁶ 6001

6002

6003

6004

6005

6006

6007

6008

6009

6010

Example 5 Evaluation of Growth Inhibitory Effect Against Cancer CellLines

Renal cancer cell line ACHN cell or colorectal cancer cell line HT-29cells were cultured in a 96 well plate at 1.0×10⁴ cells/90 μL/well for24 hrs, then a test substance dissolved in DMSO (dimethyl sulfoxide) wasadded. After 18 hrs, 3H-thymidine (0.25 μCi/well) was added and thecells were cultured for 6 hrs. Using a cell harvester, the cells wererecovered on a UniFilter-96 GF/B glass filter and the ³H radioactivityuptaken by the cells was measured by TopCount (Packard). As a control,DMSO was used and the activity of the test substance was expressed inthe concentration (IC₅₀) necessary for inhibiting ³H radioactivityuptaken by the cell to 50% of that of the control group. Themeasurements were made in triplicate.

The results are shown in Tables 5-1 to 5-8 according to the following.

A: not less than 0.1 μM and less than 1 μMB: not less than 0.01 μM and less than 0.1 μMC: less than 0.01 μM

TABLE 5-1 IC₅₀ Example ACHN HT-29 No. cell cell 1-1  B C 1-2  A 1-7  A1-11  A 1-55  A 1-88  A A 1-89  A B 1-95  A 1-96  A 1-97  A 1-99  A1-100 A 1-106 A A 1-111 A 1-112 A B 1-113 A A 1-114 A A 1-116 A 1-117 A1-126 A 1-127 A 1-129 A 1-132 A 1-133 A 1-136 A 1-138 A 1-140 A 1-142 A1-143 A 1-151 A 1-152 A B 1-153 A 1-156 A 1-159 A 1-163 A 1-164 B

TABLE 5-2 IC₅₀ Example ACHN HT-29 No. cell cell 1-165 A 1-166 B 1-168 B1-171 B 1-175 A 1-176 A B 1-183 A 1-185 A B 1-186 B 1-188 A B 1-189 A1-190 A 1-191 A B 1-192 A B 1-193 A C 1-199 A B 1-200 A B 1-201 A 1-205A C 1-206 A 1-207 B C 1-208 B C 1-211 A 1-212 A C 1-213 A B 1-214 B1-215 A 1-216 A 1-217 A 1-218 B 1-219 A B 1-221 B C 1-222 A B 1-223 A B1-224 A C 1-225 A

TABLE 5-3 IC₅₀ Example ACHN HT-29 No. cell cell 1-226 A B 1-227 B 1-228A B 1-229 A 1-230 A 1-232 A B 1-233 A 1-234 A 1-235 A 1-236 A 1-240 B B1-242 A B 1-243 A B 1-244 A 1-245 B C 1-246 A B 1-249 A B 1-252 B 1-253A B 1-255 A 1-257 C C 1-258 A 1-259 A C 1-260 C C 1-262 B C 1-263 A C1-264 A B 1-265 A B 1-266 A C 1-267 A B 1-268 B B 1-270 A B 1-271 B C1-272 B B 1-273 A 3-1  A A

TABLE 5-4 IC₅₀ Example ACHN HT-29 No. cell cell 1-274 C C 1-275 B C1-276 A B 1-277 B 1-278 A B 1-279 A B 1-282 A B 1-283 A B 1-284 A B1-285 B B 1-286 B C 1-287 A B 1-288 B 1-289 C C 1-290 B C 1-292 B 1-293A A 1-294 B 1-295 A B 1-296 A C 1-297 B C 1-298 B C 1-299 A B 1-301 A B1-302 B C 1-303 A B 1-304 A B 1-305 B 1-307 A B 1-308 A B 1-309 B C1-310 B C 1-311 C C 1-313 B 1-313 B 1-315 A B

TABLE 5-5 IC₅₀ Example ACHN HT-29 No. cell cell 1-316 A B 1-317 A B1-318 A C 1-319 C C 1-320 B C 1-321 B C 1-322 B C 1-324 B 1-325 A B1-326 A 1-327 A B 1-328 A B 1-333 B C 1-334 A 1-335 A B 1-336 B C 1-337B C 1-338 B C 1-339 A 1-340 B C 1-341 B C 1-342 A C 1-343 A B 3-4  B C3-5  B C 3-6  A C 3-7  C C 3-8  B C 4-1  C C 4-2  C C 4-3  B C 4-4  A4-5  A B 4-6  B C 4-7  A 4-9  B C

TABLE 5-6 IC₅₀ Example ACHN HT-29 No. cell cell 4-10 A B 4-11 B C 4-12 BC 4-13 A 4-15 B C 4-16 C C 4-19 B C 4-20 B C 4-21 B C 4-25 B C 4-26 B C4-27 A 4-33 C C 4-34 C C 4-37 A B 4-39 A 4-40 B C 4-41 B B 4-42 B C 4-43A B 4-44 A B 4-45 A B 4-46 A B 4-47 A 4-48 B C 4-49 B C 4-50 A B 4-51 BC 4-52 A A 4-53 A B 4-54 C C 4-55 B C 4-56 A B 4-57 A 4-58 B C 4-59 B C

TABLE 5-7 IC₅₀ Example ACHN HT-29 No. cell cell 4-60 B C 4-61 B B 4-63 B4-64 A B 4-66 A B 4-67 B C 4-70 B C 4-71 A B 4-72 B C 4-73 B C 4-74 B C4-75 B 4-76 B C 4-77 B C 4-78 A B 4-80 B C 4-81 B C 4-82 B C 4-85 A 4-87A B 4-88 C C 4-89 A B 4-90 A B 4-91 B C 4-92 B C 4-93 B C 4-94 A B 4-95A B 4-96 A B 4-97 B C 4-98 B C 4-99 A C  4-101 B C  4-102 A B  4-103 A C 4-104 C C

TABLE 5-8 IC₅₀ Example ACHN HT-29 No. cell cell 4-105 B C 4-106 B C4-107 B C 4-108 B C 4-109 B C 4-110 B C 4-111 A B 4-112 A C 4-113 C C4-114 B C 4-115 B C 4-116 A C 4-117 A C 4-118 B C 4-119 B C 4-120 B C4-121 B C 4-122 B C 4-123 A C 4-124 B C 4-125 C C 4-126 C C 4-127 B C4-128 B C 4-133 A 4-135 A 4-138 A 4-140 A 4-145 A 4-146 A 4-147 A 4-148A

Example 6 Evaluation of p15 Induction Activity

ACHN cells or HT-29 cells were cultured in a 6 well plate at 2.5×10⁵cells/1.8 mL/well for 24 hrs, then a test substance (0.1 kM) dissolvedin DMSO was added. After 24 hrs, cells were detached using trypsin-EDTA(ethylene diamine tetraacetic acid) and solubilized with NuPAGE LDSsample buffer (Invitrogen). Using an RC DC protein assay kit (BIO-RAD),the protein concentration of the sample was quantitated, and a sample inan amount corresponding to 10 μg of BSA (bovine serum albumin) wasanalyzed by Western blotting using an anti-p15 antibody. The density ofthe band stained with the anti-p15 antibody was measured by adensitometer to quantify the amount of p15 protein. As a control, DMSOwas used and the test was performed with n=2 and the average proteinamount was determined.

The results are shown in Tables 6-1 to 6-6 according to the following.

+: As compared to DMSO, not less than 1.5-fold induction of p15 protein

TABLE 6-1 Example Induction of No. p15 protein 1-1  + 1-4  + 1-6  +1-7  + 1-8  + 1-9  + 1-11 + 1-12 + 1-16 + 1-17 + 1-26 + 1-33 + 1-34 +1-35 + 1-36 + 1-37 + 1-38 + 1-40 + 1-43 + 1-46 + 1-49 + 1-51 + 1-53 +1-55 + 1-65 + 1-77 + 1-78 + 1-79 + 1-80 + 1-81 + 1-84 + 1-85 + 1-86 +1-88 + 1-89 + 1-92 +

TABLE 6-2 Example Induction of No. p15 protein 1-93  + 1-94  + 1-95  +1-96  + 1-97  + 1-99  + 1-100 + 1-102 + 1-103 + 1-104 + 1-106 + 1-107 +1-108 + 1-109 + 1-110 + 1-111 + 1-112 + 1-113 + 1-114 + 1-116 + 1-117 +1-126 + 1-127 + 1-131 + 1-132 + 1-133 + 1-136 + 1-137 + 1-138 + 1-142 +1-143 + 1-146 + 1-151 + 1-152 + 1-153 + 1-154 +

TABLE 6-3 Example Induction of No. p15 protein 1-156 + 1-157 + 1-162 +1-163 + 1-165 + 1-166 + 1-167 + 1-168 + 1-172 + 1-173 + 1-175 + 1-176 +1-183 + 1-185 + 1-186 + 1-188 + 1-191 + 1-192 + 1-193 + 1-199 + 1-200 +1-205 + 1-207 + 1-208 + 1-212 + 1-213 + 1-218 + 1-219 + 1-221 + 1-222 +1-223 + 1-224 + 1-226 + 1-240 + 1-242 + 1-243 + 1-245 + 1-246 +

TABLE 6-4 Example Induction of No. p15 protein 1-264 + 1-265 + 1-266 +1-268 + 1-271 + 1-272 + 1-282 + 1-283 + 1-284 + 1-285 + 1-286 + 1-287 +1-289 + 1-290 + 1-293 + 1-295 + 1-296 + 1-297 + 1-298 + 1-301 + 1-317 +1-318 + 1-319 + 1-320 + 1-321 + 1-322 + 1-325 + 1-327 + 1-328 + 1-333 +1-336 + 1-337 + 1-338 + 1-340 + 1-341 + 1-342 + 3-4  + 3-6  +

TABLE 6-5 Example Induction of No. p15 protein 3-7  + 3-8  + 4-1  +4-2  + 4-3  + 4-6  + 4-9  + 4-10 + 4-11 + 4-12 + 4-15 + 4-16 + 4-21 +4-43 + 4-45 + 4-48 + 4-49 + 4-50 + 4-51 + 4-53 + 4-54 + 4-55 + 4-56 +4-58 + 4-59 + 4-60 + 4-61 + 4-64 + 4-66 + 4-67 + 4-70 + 4-71 + 4-72 +4-73 + 4-74 + 4-76 + 4-77 + 4-78 +

TABLE 6-6 Example Induction of No. p15 protein 4-80  + 4-81  + 4-82  +4-88  + 4-89  + 4-90  + 4-91  + 4-92  + 4-93  + 4-97  + 4-98  + 4-101 +4-102 + 4-103 + 4-104 + 4-105 + 4-106 + 4-107 + 4-108 + 4-109 + 4-110 +4-111 + 4-112 + 4-113 + 4-114 + 4-115 + 4-116 + 4-117 + 4-118 + 4-119 +4-120 + 4-121 + 4-122 + 4-123 + 4-124 + 4-125 + 4-126 + 4-127 + 4-128 +

Example 7 Cell Cycle Analysis

ACHN cells or HT-29 cells were cultured in a 6 well plate at 2.5×10⁵cells/1.8 mL/well for 24 hrs, then a test substance (less than 10 DM)dissolved in DMSO was added. After 24 hrs, cells were detached usingtrypsin-EDTA and the DNA content of single cell was analyzed by flowcytometry method using a CycleTEST PLUS (BECKTON DICKINSON) kit, and theproportion of the cells in the G0/G1 phase·S phase·G2/M phase wascalculated. As a control, DMSO was used and the test was performed withn=2.

The results are shown in Tables 7-1 and 7-2 according to the following.

G1: the ratio of the cells in the G0/G1 phase was not less than 1.2-foldas compared to that of DMSO.

TABLE 7-1 Example CELL RATIO OF No. G0/G1 PHASE 1-2  G1 1-4  G1 1-6  G11-7  G1 1-9  G1 1-11 G1 1-21 G1 1-25 G1 1-26 G1 1-33 G1 1-34 G1 1-38 G11-43 G1 1-49 G1 1-50 G1 1-51 G1 1-55 G1 1-69 G1 1-77 G1 1-78 G1 1-84 G11-85 G1 1-86 G1 1-88 G1 1-89 G1 1-90 G1 1-91 G1 1-92 G1 1-93 G1 1-94 G11-95 G1 1-97 G1 1-99 G1  1-100 G1  1-101 G1  1-102 G1  1-103 G1  1-104G1

TABLE 7-2 Example CELL RATIO OF No. G0/G1 PHASE 3-7  G1 4-1  G1 4-3  G14-16 G1 4-70 G1 4-82 G1  4-104 G1  4-126 G1

Example 8 Evaluation on the Nude-Mouse Xenograft Model

HT-29 cells (5.0×10⁶ cells/100 μL/head, suspended in HBSS (Hanks'solution)) in the logarithmic growth phase were implanted in a mouse(Balb/c-nu/nu) at the right lateral abdomen under ether anesthesia.After 5 days of implantation, the long diameter and short diameter ofthe tumor were measured, and the mice were divided into groups such thateach group has an equivalent average tumor volume. For grouping, agrouping soft (general grouping system (Visions) was used. From the nextday of the grouping, a test substance suspended in 0.5% MC (methylcellulose) was repeatedly orally administered twice a day for 10 days(30 mg/kg). The tumor volume was measured twice a week and used as anindex of antitumor activity. As a control, 0.5% MC was used and the testwas performed with n=6-8.

The index (T/C (%)) of the antitumor activity was calculated accordingto the following formula.

T/C (%)=(The average tumor volume of the group treated with a testsubstance)/(The average tumor volume of the Vehicle group)×100

The tumor volume was calculated according to the following formula.

Tumor volume (mm³)=L×W×W/2 (L: long diameter (mm) of tumor, W: shortdiameter (mm) of tumor)

TABLE 8 Example T/C No. (%)  1-257 26 3-8  27 4-1  3 4-15 31 4-16 104-49 35 4-54 11 4-70 31

Example 9 p27 Protein Induction Test

ACHN cells or HT-29 cells were cultured in a 6 well plate at 2.5×10⁵cells/1.8 mL/well for 24 hrs, a test substance (0.1 μM) dissolved inDMSO was added. After 24 hrs, cells were detached using trypsin-EDTA(ethylene diamine tetraacetic acid) and solubilized with NuPAGE LDSsample buffer (Invitrogen). Using an RC DC protein assay kit (BIO-RAD),the protein concentration of the sample was quantitated, and a sample inan amount corresponding to 10 g of BSA (bovine serum albumin) wasanalyzed by Western blotting using an anti-p27 antibody. The density ofthe band stained with the anti-p27 antibody was measured by adensitometer to quantify the amount of p27 protein. As a control, DMSOwas used and the test was performed with n=2 and the average proteinamount was determined.

The results are shown in Tables 9-1 to 9-4 according to the following.

+: As compared to DMSO, not less than 1.5-fold induction of p27 protein

TABLE 9-1 Example Induction of No. p27 protein 1-1  + 1-89  + 1-112 +1-114 + 1-142 + 1-152 + 1-175 + 1-182 + 1-185 + 1-186 + 1-218 + 1-219 +1-221 + 1-222 + 1-224 + 1-226 + 1-228 + 1-240 + 1-242 + 1-243 + 1-245 +1-249 + 1-253 + 1-257 + 1-259 + 1-260 + 1-262 + 1-263 + 1-264 + 1-265 +1-266 + 1-268 + 1-271 + 1-272 + 1-274 + 1-275 + 1-279 + 1-282 +

TABLE 9-2 Example Induction of No. p27 protein 1-283 + 1-284 + 1-285 +1-286 + 1-287 + 1-289 + 1-290 + 1-293 + 1-295 + 1-296 + 1-297 + 1-298 +1-299 + 1-301 + 1-302 + 1-303 + 1-307 + 1-309 + 1-310 + 1-311 + 1-315 +1-316 + 1-317 + 1-318 + 1-319 + 1-320 + 1-322 + 1-325 + 1-327 + 1-328 +1-336 + 1-337 + 1-338 + 1-340 + 1-341 + 1-342 + 3-4  + 3-5  +

TABLE 9-3 Example Induction of No. p27 protein 3-6  + 3-7  + 3-8  +4-1  + 4-2  + 4-3  + 4-6  + 4-9  + 4-10 + 4-11 + 4-12 + 4-15 + 4-16 +4-21 + 4-43 + 4-45 + 4-48 + 4-49 + 4-50 + 4-51 + 4-53 + 4-54 + 4-55 +4-56 + 4-58 + 4-59 + 4-60 + 4-61 + 4-64 + 4-66 + 4-67 + 4-70 + 4-71 +4-72 + 4-73 + 4-74 + 4-76 + 4-77 +

TABLE 9-4 Example Induction of No. p27 protein 4-78  + 4-80  + 4-81  +4-82  + 4-88  + 4-89  + 4-90  + 4-91  + 4-92  + 4-93  + 4-97  + 4-98  +4-99  + 4-101 + 4-102 + 4-103 + 4-104 + 4-105 + 4-106 + 4-107 + 4-108 +4-109 + 4-110 + 4-113 + 4-114 + 4-115 + 4-116 + 4-117 + 4-118 + 4-119 +4-120 + 4-121 + 4-122 + 4-123 + 4-124 + 4-125 + 4-126 + 4-127 + 4-128 +

Example 10 Evaluation of MEK Enzyme Inhibitory Activity

To an evaluation system where Raf (B-Raf or c-Raf) and MEK (MEK1 orMEK2) were mixed, or MEK (MEK1 or MEK2) and ERK2 were mixed was added atest substance dissolved in DMSO, and an ATP solution containing[γ-32P]-ATP was added to start the enzyme reaction. After reacting at30° C. for 20 min, the reaction mixture was subjected to SDS-PAGE(sodium dodecylsulfate-polyacrylamide gel electrophoresis) andradioactivity of phosphorylated MEK or ERK2 was measured by Bio ImagingAnalyzer (BAS2000, Fuji photo film).

With the radioactivity of the solvent added control as 100%, inhibitoryrate (%) by the test substance was determined, and IC₅₀ value wascalculated.

The test was performed with n=1 and the average values of two or threetimes of testing are shown. The results are summarized in Table 10.

TABLE 10 IC₅₀ of various enzyme reaction system (μM) enzyme Example1-257 Example 4-1 B-Raf 0.0060 0.0067 MEK1 B-Raf 0.0188 0.0128 MEK2c-Raf — — MEK1 c-Raf 0.0078 0.0130 MEK2 MEK1 1.3 0.290 ERK2 MEK2 1.60.190 ERK2

Example 11 Evaluation on the Mouse Collagen Arthritis Model

Bovine type II collagen (100 μg) was resuspended with Freund's completeadjuvant and intracutaneously administered (initial immunization) to thetail head of mouse (DBA/1). Three weeks later, the same collagen wasgiven to the tail head as boost, whereby multiple arthritis was induced.The test substance was oral administered forcibly once a day for 38 daysfrom immediately before the initial immunization, and arthritis scoreafter boost was calculated twice a week to examine the arthritis onsetsuppressing effect. For arthritis scores, the level of swelling of eachof the four limbs of the mice was scored in 4 levels, and the average ofthe scores of four limbs was taken as the arthritis score of eachindividual. The test was performed with n=16.

The arthritis score at 17 days after boost (after consecutiveadministration for 38 days) was 2.2 for the medium administration group,and 0.57 (p<0.001, wilcoxson test) for the 1 mg/kg acetic acid solvateof compound of Example 4-1 administration group, thus showing asignificant suppressive effect on the arthritis onset.

Example 12 Evaluation on Inflammatory Cytokine Production

The compounds of Example 4-1 and Example 4-16 suppressed production ofTNF-α or IL-6 upon stimulation of human 20 peripheral blood-derivednomonuclear cell (PBMC) with LPS. The MS and NMR data of the Examplecompounds shown in the above-mentioned Table 1-1 to Table 4-25 are shownbelow.

Example 1-1

MS ESI m/e: 590, 592 (M+H), 588, 590 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 0.99-1.08 (m, 2H),2.64-2.70 (m, 4H), 3.02 (s, 3H), 5.36 (s, 1H), 7.13 (d, J=9.0 Hz, 1H),7.24-7.30 (m, 2H), 7.43-7.54 (m, 3H), 7.74 (d, J=9.0 Hz, 1H), 10.00(brs, 1H), 10.53 (brs, 1H).

Example 1-2 Example 1-3 Example 1-4

MS ESI m/e: 470, 471 (M+H), 473, 474, 469 (M−H), 470, 471.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.68 (s, 3H), 5.47 (s, 1H), 7.24-7.63 (m,14H), 10.63 (brs, 1H).

Example 1-5

MS ESI m/e: 470, 471 (M+H), 473, 474, 469 (M−H), 470, 471.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.68 (s, 3H), 5.60 (s, 1H), 7.25-7.57 (m,14H), 10.52 (brs, 1H).

Example 1-6

MS ESI m/e: 451 (M+H), 449 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 2.34 (s, 3H), 2.88 (s, 3H), 5.79 (s, 1H),7.08-7.18 (m, 4H), 7.27-7.32 (m, 2H), 7.37-7.54 (m, 8H), 10.24 (s, 1H).

Example 1-7

MS ESI m/e: 480 (M+H).

¹H-NMR (CDCl₃, 400 MHz) δ 2.87 (s, 3H), 2.95 (s, 6H), 5.66 (s, 1H),6.67-6.73 (m, 2H), 7.05-7.11 (m, 2H), 7.27-7.32 (m, 2H), 7.37-7.55 (m,8H), 10.24 (s, 1H).

Example 1-8

MS ESI m/e: 455 (M+H), 453 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 2.88 (s, 3H), 5.69 (s, 1H), 7.03-7.10 (m, 2H),7.17-7.23 (m, 2H), 7.27-7.32 (m, 2H), 7.37-7.55 (m, 8H), 10.24 (s, 1H).

Example 1-9

MS ESI m/e: 467 (M+H), 465 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 2.88 (s, 3H), 3.81 (s, 3H), 5.67 (s, 1H),6.86-6.95 (m, 2H), 7.12-7.20 (m, 2H), 7.28-7.34 (m, 2H), 7.37-7.58 (m,8H), 10.14 (s, 1H).

Example 1-10

MS ESI m/e: 485 (M+H), 483 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 2.86 (s, 3H), 4.32 (d, J=4.0 Hz, 2H), 5.39 (s,1H), 7.23-7.31 (m, 6H), 7.34-7.38 (m, 2H), 7.39-7.52 (m, 6H), 9.03 (t,J=6.0 Hz, 1H).

Example 1-11

MS ESI m/e: 515, 517 (M+H), 513, 515 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 2.67 (s, 3H), 5.56 (s, 1H), 7.25-7.29 (m,2H), 7.34-7.38 (m, 2H), 7.41-7.55 (m, 8H), 7.57-7.61 (m, 2H), 10.48 (s,1H).

Example 1-12 Example 1-13 Example 1-14

MS ESI m/e: 485 (M+H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 2.74 (s, 3H), 3.22 (s, 3H), 6.03 (s, 1H),6.99-7.05 (m, 4H), 7.21-7.25 (m, 2H), 7.32-7.40 (m, 3H), 7.44-7.54 (m,5H).

Example 1-15

MS ESI m/e: 443 (M+H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.17-1.95 (m, 11H), 2.63 (s, 3H), 5.28 (s,1H), 7.31-7.55 (m, 10H), 8.76 (d, J=6.0 Hz, 1H).

Example 1-16

MS ESI m/e: 481 (M+H), 479 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 2.88 (s, 3H), 5.69 (s, 1H), 5.99 (s, 2H),6.85-6.82 (m, 3H), 7.28-7.34 (m, 2H), 7.37-7.58 (m, 8H), 10.12 (s, 1H).

Example 1-17

MS ESI m/e: 505, 507 (M+H), 503, 505 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 2.90 (s, 3H), 5.87 (s, 1H), 7.07-7.11 (m, 1H),7.26-7.31 (m, 2H), 7.35-7.56 (m, 10H), 10.45 (s, 1H).

Example 1-18

MS ESI m/e: 499 (M+H), 497 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.56 (t, J=7.5 Hz, 3H), 1.05-1.12 (m, 2H),3.30-3.40 (m, 2H), 5.54 (s, 1H), 7.31-7.56 (m, 14H), 10.52 (s, 1H).

Example 1-19

MS ESI m/e: 513 (M+H), 511 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62 (s, 3H), 0.64 (s, 3H), 1.04 (d, J=6.0Hz, 1H), 1.94-2.06 (m, 1H), 3.13 (brs, 1H), 5.56 (s, 1H), 7.32-7.60 (m,14H), 10.58 (s, 1H).

Example 1-20

MS ESI m/e: 515 (M+H), 513 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.04 (t, J=6.0 Hz, 2H), 3.09 (s, 3H), 3.61(t, J=4.5 Hz, 2H), 5.53 (s, 1H), 7.32-7.60 (m, 14H), 10.52 (s, 1H).

Example 1-21

MS ESI m/e: 465 (M+H), 463 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 1.19 (t, J=8.0 Hz, 3H), 2.61 (q, J=8.0 Hz,2H), 2.66 (s, 3H), 5.46 (s, 1H), 7.17-7.21 (m, 2H), 7.25-7.29 (m, 2H),7.34-7.38 (m, 2H), 7.41-7.55 (m, 8H), 10.37 (s, 1H).

Example 1-22

MS ESI m/e: 451 (M+H), 449 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 2.21 (s, 3H), 2.66 (s, 3H), 5.12 (s, 1H),7.18-7.55 (m, 14H), 10.22 (s, 1H).

Example 1-23

MS ESI m/e: 513 (M+H), 511 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 2.68 (s, 3H), 5.65 (s, 1H), 7.33-7.56 (m,15H), 7.66-7.74 (m, 4H), 10.56 (s, 1H).

Example 1-24

MS ESI m/e: 467 (M+H), 465 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 2.89 (s, 3H), 3.82 (s, 3H), 5.83 (s, 1H),6.91-6.98 (m, 2H), 7.13-7.19 (m, 1H), 7.27-7.33 (m, 2H), 7.37-7.54 (m,9H), 10.21 (s, 1H).

Example 1-25

MS ESI m/e: 479 (M+H), 477 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 1.25 (d, J=6.7 Hz, 6H), 2.85-2.95 (m, 1H),2.88 (s, 3H), 5.80 (s, 1H), 7.12-7.17 (m, 2H), 7.19-7.24 (m, 2H),7.27-7.32 (m, 2H), 7.37-7.55 (m, 8H), 10.24 (s, 1H).

Example 1-26

MS ESI m/e: 505, 507 (M+H), 503, 505 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 2.89 (s, 3H), 5.70 (s, 1H), 7.22-7.32 (m, 3H),7.37-7.55 (m, 10H), 10.39 (s, 1H).

Example 1-27

MS ESI m/e: 520 (M+H).

¹H-NMR (CDCl₃, 400 MHz) δ 1.54-1.62 (m, 4H), 1.67-1.75 (m, 4H), 2.87 (s,3H), 3.14 (t, J=5.6 Hz, 2H), 5.70 (s, 1H), 6.87-6.93 (m, 2H), 7.06-7.11(m, 2H), 7.27-7.32 (m, 2H), 7.37-7.54 (m, 8H), 10.09 (s, 1H).

Example 1-28

MS ESI m/e: 508 (M+H), 506 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 1.16 (t, J=7.1 Hz, 6H), 2.87 (s, 3H), 3.34 (q,J=7.1 Hz, 4H), 5.65 (s, 1H), 6.60-6.65 (m, 2H), 7.00-7.06 (m, 2H),7.27-7.31 (m, 2H), 7.36-7.54 (m, 8H), 9.98 (s, 1H).

Example 1-29

MS ESI m/e: 527 (M+H), 525 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 2.88 (s, 3H), 3.97 (s, 2H), 5.83 (s, 1H),7.12-7.58 (m, 19H), 10.29 (s, 1H).

Example 1-30

MS ESI m/e: 522 (M+H), 520 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.66 (s, 3H), 3.10-3.13 (m, 4H), 3.73-3.76(m, 4H), 5.32 (s, 1H), 7.01 (d, J=9.0 Hz, 2H), 7.15 (d, J=9.0 Hz, 2H),7.35-7.57 (m, 10H), 10.20 (brs, 1H).

Example 1-31

MS ESI m/e: 493 (M+H), 491 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.90 (t, J=8.0 Hz, 3H), 1.26-1.36 (m, 2H),1.52-1.60 (m, 2H), 2.58 (t, J=8.0 Hz, 2H), 2.66 (s, 3H), 5.46 (s, 1H),7.18 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 7.35-7.37 (m, 2H),7.41-7.54 (m, 8H), 10.36 (brs, 1H).

Example 1-32

MS ESI m/e: 409 (M+H), 407 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.46 (s, 3H), 3.48 (s, 3H), 5.49 (s, 1H),7.28-7.34 (m, 4H), 7.41-7.53 (m, 5H), 10.44 (brs, 1H).

Example 1-33

MS ESI m/e: 505 (M+H), 503 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 2.67 (s, 3H), 5.78 (s, 1H), 7.34 (d, J=8.0Hz, 2H), 7.40-7.53 (m, 10H), 7.73 (d, J=8.0 Hz, 2H), 10.75 (brs, 1H).

Example 1-34

MS ESI m/e: 485 (M+H), 483 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.32 (s, 3H), 2.67 (s, 3H), 5.35 (s, 1H),7.23-7.56 (m, 13H), 10.48 (brs, 1H).

Example 1-35

MS ESI m/e: 409 (M+H), 407 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.61 (s, 3H), 3.26 (s, 3H), 5.50 (s, 1H),7.35 (d, J=6.0 Hz, 2H), 7.44-7.54 (m, 5H), 7.49 (d, J=6.0 Hz, 2H), 10.62(brs, 1H).

Example 1-36

MS ESI m/e: 431 (M+H).

¹H-NMR (CDCl₃, 400 MHz) δ 1.00 (s, 9H), 2.86 (s, 3H), 2.92 (d, J=8.0 Hz,2H), 5.43 (s, 1H), 7.24-7.29 (m, 2H), 7.34-7.53 (m, 8H), 8.78 (t, J=6.0Hz, 1H).

Example 1-37

MS ESI m/e: 481 (M+H), 479 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.70 (s, 3H), 5.85 (s, 1H), 7.36-7.54 (m,10H), 7.43 (d, J=9.0 Hz, 2H), 7.97 (d, J=9.0 Hz, 2H), 10.81 (brs, 1H).

Example 1-38

MS ESI m/e: 465 (M+H), 463 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 1.18 (t, J=7.5 Hz, 3H), 2.63 (q, J=7.5 Hz,2H), 2.88 (s, 3H), 5.43 (s, 1H), 7.20-7.36 (m, 6H), 7.39-7.57 (m, 8H),10.07 (s, 1H).

Example 1-39

MS ESI m/e: 507 (M+H), 505 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.78 (t, J=7.3 Hz, 6H), 1.44-1.77 (m, 4H),2.25-2.38 (m, 1H), 2.89 (s, 3H), 5.85 (s, 1H), 7.10-7.19 (m, 4H),7.28-7.34 (m, 2H), 7.38-7.57 (m, 8H), 10.28 (s, 1H).

Example 1-40

MS ESI m/e: 535 (M+H), 533 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.85 (t, J=7.4 Hz, 6H), 1.08-1.24 (m, 4H),1.45-1.64 (m, 4H), 2.45-2.58 (m, 1H), 2.89 (s, 3H), 5.84 (s, 1H),7.10-7.18 (m, 4H), 7.28-7.34 (m, 2H), 7.38-7.57 (m, 8H), 10.27 (s, 1H).

Example 1-41

MS ESI m/e: 497 (M+H), 495 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.79-1.00 (m, 4H), 1.70-1.78 (m, 1H), 5.73 (s,1H), 7.12-7.18 (m, 2H), 7.26-7.34 (m, 4H), 7.35-7.55 (m, 8H), 10.35 (s,1H).

Example 1-42

MS ESI m/e: 539, 541 (M+H), 537, 539 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 2.92 (s, 3H), 5.80 (s, 1H), 7.14-7.19 (m, 2H),7.19-7.24 (m, 2H), 7.30-7.36 (m, 4H), 7.45-7.51 (m, 4H), 10.24 (s, 1H).

Example 1-43

MS ESI m/e: 485 (M+H), 483 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.57 (s, 3H), 2.76 (s, 3H), 6.93 (d, J=9.0Hz, 2H), 7.31-7.54 (m, 12H), 10.07 (brs, 1H).

Example 1-44

MS ESI m/e: 477 (M+H), 475 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.07-1.85 (m, 11H), 2.60 (s, 3H), 4.65-4.65(m, 1H), 5.49 (s, 1H), 7.35-7.54 (m, 5H), 10.63 (brs, 1H).

Example 1-45

MS ESI m/e: 485 (M+H), 483 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.63 (s, 3H), 5.10 (brs, 2H), 5.51 (s, 1H),7.24-7.56 (m, 14H), 10.57 (s, 1H).

Example 1-46

MS ESI m/e: 452 (M+H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.67 (s, 3H), 5.47 (s, 1H), 7.19 (d, J=9.0Hz, 2H), 7.29 (d, J=6.0 Hz, 2H), 7.35-7.40 (m, 2H), 7.41-7.57 (m, 8H),10.40 (s, 1H).

Example 1-47

MS ESI m/e: 421 (M+H), 419 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 2.19-2.30 (m, 2H), 4.09-4.20 (m, 4H), 5.73 (s,1H), 7.11-7.19 (m, 2H), 7.23-7.36 (m, 4H), 7.45-7.60 (m, 3H), 10.49 (s,1H).

Example 1-48

MS ESI m/e: 453 (M+H), 451 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.65 (s, 3H), 5.08 (s, 1H), 6.07 (brs, 2H),6.52 (d, J=9.0 Hz, 1H), 7.29-7.57 (m, 11H), 7.80 (d, J=3.0 Hz, 1H), 9.94(brs, 1H).

Example 1-49

MS ESI m/e: 466 (M+H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.67 (s, 3H), 2.86 (s, 3H), 5.50 (s, 1H),7.33-7.57 (m, 14H), 10.44 (brs, 1H).

Example 1-50

MS ESI m/e: 479 (M+H), 477 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.90 (t, J=7.3 Hz, 3H), 1.51-1.66 (m, 2H),2.57 (t, J=7.5 Hz, 2H), 2.88 (s, 3H), 5.43 (s, 11H), 7.17-7.30 (m, 4H),7.30-7.37 (m, 2H), 7.39-7.58 (m, 8H), 10.07 (s, 1H).

Example 1-51

MS ESI m/e: 493 (M+H), 491 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.88 (t, J=6.0 Hz, 3H), 1.26-1.38 (m, 2H),1.49-1.61 (m, 2H), 2.55-2.61 (m, 2H), 2.88 (s, 3H), 5.43 (s, 1H),7.14-7.34 (m, 6H), 7.39-7.56 (m, 8H), 10.07 (brs, 1H).

Example 1-52

MS ESI m/e: 528 (M+H), 526 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 2.15 (s, 6H), 2.12-2.22 (m, 2H), 3.72 (t,J=6.5 Hz, 2H), 5.81 (s, 1H), 7.15-7.21 (m, 2H), 7.26-7.35 (m, 4H),7.40-7.56 (m, 8H), 10.35 (s, 1H).

Example 1-53

MS ESI m/e: 485 (M+H), 483 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 2.24 (s, 3H), 2.88 (s, 3H), 5.39 (s, 1H),7.17-7.20 (m, 2H), 7.28-7.33 (m, 2H), 7.37-7.55 (m, 9H), 10.04 (s, 1H).

Example 1-54

MS ESI m/e: 472 (M+H), 470 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 2.68 (s, 3H), 5.50 (s, 1H), 7.34-7.38 (m,2H), 7.41-7.57 (m, 9H), 7.87 (dd, J=4.0, 8.0 Hz, 1H), 8.37 (d, J=4.0 Hz,1H), 10.49 (s, 1H).

Example 1-55

MS ESI m/e: 494 (M+H), 492 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.15 (s, 3H), 2.64 (s, 3H), 2.90 (s, 6H),4.92 (s, 1H), 6.63 (dd, J=3.0, 9.0 Hz, 1H), 6.69 (d, J=3.0 Hz, 1H), 7.03(d, J=9.0 Hz, 1H), 7.36-7.57 (m, 10H), 9.89 (s, 1H).

Example 1-56

MS ESI m/e: 497 (M+H), 495 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 4.24 (d, J=4.2 Hz, 2H), 4.87 (d, J=16.9 Hz,1H), 5.02 (d, J=10.4 Hz, 1H), 5.40-5.51 (m, 1H), 5.83 (s, 1H), 7.16-7.21(m, 2H), 7.26-7.30 (m, 2H), 7.31-7.36 (m, 2H), 7.36-7.41 (m, 2H),7.43-7.55 (m, 6H), 10.40 (s, 1H).

Example 1-57

MS ESI m/e: 482 (M+H), 480 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 2.93 (s, 3H), 6.20 (s, 1H), 7.28-7.33 (m, 2H),7.35-7.44 (m, 4H), 7.46-7.59 (m, 6H), 8.20-8.27 (m, 2H), 10.95 (s, 1H).

Example 1-58

MS ESI m/e: 451 (M+H), 449 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.83 (d, J=9.0 Hz, 6H), 1.90-2.04 (m, 1H),3.45 (s, 3H), 3.98 (d, J=9.0 Hz, 2H), 5.50 (s, 1H), 7.28-7.34 (m, 4H),7.43-7.55 (m, 5H), 10.30 (brs, 1H).

Example 1-59

MS ESI m/e: 444 (M+H), 442 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 3.14 (s, 3H), 5.22 (s, 1H), 6.96-7.03 (m, 2H),7.17-7.41 (m, 5H), 7.41-7.55 (m, 3H), 7.60 (d, J=3.7 Hz, 1H), 7.89 (d,J=3.7 Hz, 1H), 11.57 (s, 1H).

Example 1-60

MS ESI m/e: 457 (M+H), 455 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 5.70 (s, 1H), 7.14-7.12 (m, 2H), 7.30-7.43 (m,6H), 7.43-7.65 (m, 6H), 10.48 (s, 1H).

Example 1-61

MS ESI m/e: 466 (M+H), 464 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 2.95 (s, 3H), 5.56 (s, 1H), 6.65-6.75 (m, 2H),7.02-7.14 (m, 2H), 7.29-7.67 (m, 10H), 10.18 (s, 1H).

Example 1-62

MS ESI m/e: 506 (M+H), 504 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 2.96 (6H, s), 4.23 (d, J=4.7 Hz, 2H), 4.88 (d,J=17.3 Hz, 1H), 5.02 (d, J=10.6 Hz, 1H), 5.40-5.55 (m, 1H), 5.69 (s,1H), 6.68-6.75 (m, 2H), 7.07-7.14 (m, 2H), 7.27-7.33 (m, 2H), 7.37-7.56(m, 8H), 10.10 (s, 1H).

Example 1-63

MS ESI m/e: 472 (M+H).

¹H-NMR (DMSO-ds, 300 MHz) δ 2.72 (s, 3H), 7.16 (d, J=9.0 Hz, 1H),7.34-7.42 (m, 2H), 7.43-7.60 (m, 10H), 7.82 (dd, J=3.0, 6.0 Hz, 1H),8.42 (d, J=3.0 Hz, 1H), 11.68 (s, 1H).

Example 1-64

MS ESI m/e: 487 (M+H).

¹H-NMR (CDCl₃, 400 MHz) δ 2.94 (s, 3H), 3.12 (s, 6H), 7.26-7.32 (m, 2H),7.34-7.54 (m, 8H), 7.68 (s, 1H), 9.00 (d, J=4.8 Hz, 1H), 10.26 (d, J=5.8Hz, 1H).

Example 1-65

MS ESI m/e: 480 (M+H), 478 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.24 (t, J=7.3 Hz, 3H), 2.68 (s, 3H), 3.27(q, J=7.3 Hz, 2H), 5.53 (s, 1H), 7.29-7.60 (m, 16H), 10.46 (s, 1H).

Example 1-66

MS ESI m/e: 478 (M+H), 477 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.16 (d, J=6.8 Hz, 6H), 2.65 (s, 3H),3.05-3.15 (m, 1H), 5.00 (s, 1H), 7.27-7.54 (m, 14H), 10.19 (brs, 1H).

Example 1-67

MS ESI m/e: 485 (M+H), 483 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.56 (t, J=7.0 Hz, 3H), 3.55 (q, 2H, J=7.0Hz), 5.53 (s, 1H), 7.10-7.13 (m, 2H), 7.32-7.56 (m, 12H), 10.49 (brs,1H).

Example 1-68

MS ESI m/e: 528 (M+H), 526 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 2.15 (s, 6H), 2.88 (s, 3H), 3.31 (s, 2H), 5.65(s, 1H), 7.21-7.54 (m, 13H), 10.50 (s, 1H).

Example 1-69

MS ESI m/e: 493 (M+H), 491 (M−H).

¹H-NMR (DMSO-ds, 300 MHz) δ 0.84 (d, J=6.6 Hz, 6H), 1.78-1.88 (m, 1H),2.45 (d, J=7.2 Hz, 2H), 2.67 (s, 3H), 5.15 (s, 1H), 7.20-7.53 (m, 14H),10.24 (brs, 1H).

Example 1-70

MS ESI m/e: 499, 501 (M+H), 497, 499 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.37 (s, 3H), 2.38 (s, 3H), 2.70 (s, 3H),5.54 (s, 1H), 7.21-7.50 (m, 12H), 10.51 (brs, 1H).

Example 1-71

MS ESI m/e: 507, 508 (M+H), 505, 506 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.85 (d, J=6.5 Hz, 6H,), 1.37-1.42 (m, 2H),1.49-1.53 (m, 1H), 2.50-2.58 (m, 2H), 2.67 (s, 3H), 5.12 (s, 1H),7.24-7.55 (m, 14H), 10.23 (brs, 1H).

Example 1-72

MS ESI m/e: 499 (M+H), 497 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 2.12-2.44 (m, 6H), 2.84 (s, 3H), 5.83 (brs,1H), 7.05-7.48 (m, 12H), 10.47-10.57 (m, 1H).

Example 1-73

MS ESI m/e: 522 (M+H), 520 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.91 (t, J=7.3 Hz, 3H), 1.49-1.66 (m, 2H),2.50 (t, J=7.7 Hz, 2H), 2.87 (s, 3H), 2.95 (s, 6H), 5.33 (s, 1H),6.54-6.63 (m, 2H), 7.01-7.08 (m, 1H), 7.30-7.37 (m, 2H), 7.38-7.58 (m,8H), 9.80 (s, 1H).

Example 1-74

MS ESI m/e: 506 (M+H), 504 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 1.91-2.03 (m, 2H), 2.73 (t, J=6.4 Hz, 2H),2.87 (s, 3H), 2.88 (s, 3H), 3.22 (t, J=5.7 Hz, 2H), 5.68 (s, 1H), 6.54(d, J=8.4 Hz, 1H), 6.79-6.85 (m, 1H), 6.87-6.93 (m, 1H), 7.28-7.34 (m,2H), 7.36-7.58 (m, 8H), 10.00 (s, 1H).

Example 1-75

MS ESI m/e: 531, 533 (M+H), 529, 531 (M−H).

¹H-NMR (DMSO-ds, 300 MHz) δ 2.63 (s, 3H), 3.72 (s, 3H), 3.73 (s, 3H),5.45 (s, 1H), 6.97 (t, J=9.1 Hz, 4H), 7.16-7.42 (m, 8H), 10.46 (brs,1H).

Example 1-76

MS ESI m/e: 499, 501 (M+H), 497, 499 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.26 (s. 3H), 2.27 (s, 3H), 2.63 (s, 3H),5.46 (s, 1H), 7.09-7.42 (m, 12H), 10.42 (brs, 1H).

Example 1-77

MS ESI m/e: 483, 485 (M+H), 481, 483 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.68 (s, 3H), 5.45 (s, 1H), 7.00-7.64 (m,10H), 10.35 (brs, 1H).

Example 1-78

MS ESI m/e: 423 (M+H), 421 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 1.30 (t, J=6.9 Hz, 3H), 2.82 (s, 3H), 4.08 (q,J=7.0 Hz, 2H), 5.77 (s, 1H), 7.19-7.25 (m, 2H), 7.31-7.39 (m, 4H),7.41-7.54 (m, 3H), 10.53 (s, 1H).

Example 1-79

MS ESI m/e: 507, 508 (M+H), 505, 503 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.64 (s, 3H), 5.46 (s, 1H), 7.23-7.51 (m,12H), 10.37 (brs, 1H).

Example 1-80

MS ESI m/e: 463 (M+H), 461 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 1.52-1.67 (m, 2H), 1.82-2.02 (m, 4H),2.04-2.20 (m, 2H), 2.80 (s, 3H), 5.21-5.37 (m, 1H), 5.75 (s, 1H),7.18-7.28 (m, 2H), 7.30-7.56 (m, 7H), 10.54 (s, 1H).

Example 1-81

MS EST m/e: 437 (M+H), 435 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 1.51 (d, J=7.0 Hz, 6H), 2.81 (s, 3H),5.09-5.23 (m, 1H), 5.75 (s, 1H), 7.18-7.28 (m, 2H), 7.29-7.55 (m, 7H),10.53 (s, 1H).

Example 1-82

MS ESI m/e: 437 (M+H), 435 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.98 (t, J=7.4 Hz, 3H), 1.66-1.79 (m, 2H),2.82 (s, 3H), 3.96 (t, J=7.6 Hz, 2H), 5.77 (s, 1H), 7.20-7.25 (m, 2H),7.32-7.40 (m, 4H), 7.41-7.54 (m, 3H), 10.54 (s, 1H).

Example 1-83

MS ESI m/e: 451 (M+H), 449 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.96 (t, J=7.4 Hz, 3H), 1.34-1.47 (m, 2H),1.62-1.73 (m, 2H), 2.81 (s, 3H), 3.99 (t, J=7.6 Hz, 2H), 5.76 (s, 1H),7.18-7.24 (m, 2H), 7.31-7.39 (m, 4H), 7.41-7.52 (m, 3H), 10.53 (s, 1H).

Example 1-84

MS ESI m/e: 435 (M+H), 433 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.81-0.90 (m, 2H), 1.14-1.24 (m, 2H),2.71-2.81 (m, 1H), 2.81 (s, 3H), 5.77 (s, 1H), 7.17-7.24 (m, 2H),7.27-7.39 (m, 4H), 7.39-7.52 (m, 3H), 10.38 (s, 1H).

Example 1-85

MS ESI m/e: 423 (M+H), 421 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.25-2.30 (m, 3H), 2.51-2.57 (m, 3H),3.26-3.31 (m, 3H), 5.48-5.52 (m, 1H), 7.24-7.55 (m, 8H), 10.74 (s, 1H).

Example 1-86

MS ESI m/e: 423 (M+H), 421 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.35 (s, 3H), 2.65 (s, 3H), 3.26 (s, 3H),5.51 (s, 1H), 7.23-7.32 (m, 3H), 7.32-7.45 (m, 3H), 7.46-7.54 (m, 2H),10.64 (s, 1H).

Example 1-87

MS ESI m/e: 423 (M+H), 421 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.37 (s, 3H), 2.63 (s, 3H), 3.26 (s, 3H),5.50 (s, 1H), 7.29-7.39 (m, 6H), 7.46-7.53 (m, 2H), 10.64 (s, 1H).

Example 1-88

MS ESI m/e: 444 (M+H), 442 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.91 (m, 2H), 1.13-1.23 (m, 2H),2.71-2.80 (m, 1H), 2.80 (s, 3H), 2.97 (s, 6H), 5.62 (s, 1H), 6.69-6.77(m, 2H), 7.08-7.16 (m, 2H), 7.29-7.35 (m, 2H), 7.38-7.52 (m, 3H), 10.07(s, 1H).

Example 1-89

MS ESI m/e: 479, 481 (M+H), 477, 479 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.91 (m, 2H), 1.15-1.26 (m, 2H),2.71-2.82 (m, 1H), 2.82 (s, 3H), 5.80 (s, 1H), 7.13-7.21 (m, 2H),7.28-7.36 (m, 2H), 7.39-7.56 (m, 5H), 10.41 (s, 1H).

Example 1-90

MS ESI m/e: 477 (M+H), 475 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 2.84 (s, 3H), 4.75 (q, J=8.4 Hz, 2H), 5.76 (s,1H), 7.19-7.28 (m, 2H), 7.31-7.42 (m, 4H), 7.43-7.57 (m, 3H), 10.20 (s,1H).

Example 1-91

MS ESI m/e: 513 (M+H), 511 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64 (t, J=6.0 Hz, 3H), 1.21-1.41 (m, 2H),2.15 (t, J=7.5 Hz, 2H), 2.76 (s, 3H), 6.93-7.07 (m, 2H), 7.27-7.37 (m,4H), 7.39-7.64 (m, 8H), 9.92 (s, 1H).

Example 1-92

MS ESI m/e: 521, 523 (M+H), 519, 521 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 2.85 (s, 3H), 4.75 (q, J=8.4 Hz, 2H), 5.78 (s,1H), 7.14-7.22 (m, 2H), 7.32-7.40 (m, 2H), 7.44-7.58 (m, 5H), 10.20 (s,1H).

Example 1-93

MS ESI m/e: 486 (M+H), 484 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 2.83 (s, 3H), 2.97 (s, 6H), 4.75 (q, J=8.4 Hz,2H), 5.61 (s, 1H), 6.67-6.81 (m, 2H), 7.08-7.18 (m, 2H), 7.32-7.40 (m,2H), 7.41-7.56 (m, 3H), 9.92 (s, 1H).

Example 1-94

MS ESI m/e: 457 (M+H), 455 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.18 (t, J=6.7 Hz, 3H), 2.66 (s, 3H), 3.93(q, J=6.7 Hz, 2H), 5.50 (s, 1H), 7.36 (d, J=9.0 Hz, 2H), 7.46-7.56 (m,4H), 7.57-7.66 (m, 2H), 10.62 (s, 1H).

Example 1-95

MS ESI m/e: 467, 469 (M+H), 465, 467 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 2.28 (s, 3H), 2.53 (s, 3H), 3.28 (s, 3H),5.51 (s, 1H), 7.23-7.35 (m, 4H), 7.38-7.44 (m, 2H), 7.58-7.65 (m, 2H),10.72 (s, 1H).

Example 1-96

MS ESI m/e: 467, 469 (M+H), 465, 467 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 1.29 (t, J=7.1 Hz, 3H), 2.81 (s, 3H), 4.07 (q,J=7.1 Hz, 2H), 5.78 (s, 1H), 7.14-7.19 (m, 2H), 7.31-7.36 (m, 2H),7.40-7.53 (m, 5H), 10.53 (s, 1H).

Example 1-97

MS ESI m/e: 432 (M+H).

¹H-NMR (CDCl₃, 400 MHz) δ 1.29 (t, J=7.1 Hz, 3H), 2.80 (s, 3H), 2.96 (s,6H), 4.07 (q, J=7.0 Hz, 2H), 5.59 (s, 1H), 6.69-6.75 (m, 2H), 7.08-7.14(m, 2H), 7.31-7.36 (m, 2H), 7.38-7.50 (m, 3H), 10.19 (s, 1H).

Example 1-98

MS ESI m/e: 435 (M+H), 433 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.80-0.91 (m, 2H), 1.25-1.35 (m, 2H),3.38-3.49 (m, 1H), 3.74 (s, 3H), 5.76 (s, 1H), 7.09-7.18 (m, 2H),7.20-7.37 (m, 4H), 7.44-7.60 (m, 3H), 10.23 (s, 1H).

Example 1-99

MS ESI m/e: 432 (M+H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.27 (s, 3H), 2.51 (s, 3H), 2.92 (s, 6H),3.27 (s, 3H), 5.21 (s, 1H), 6.76-6.84 (m, 2H), 7.06-7.14 (m, 2H),7.23-7.38 (m, 2H), 7.38-7.44 (m, 2H), 10.35 (s, 1H).

Example 1-100

MS ESI m/e: 453 (M+H), 451 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.83-0.92 (m, 2H), 1.14-1.24 (m, 2H),2.74-2.83 (m, 1H), 2.86 (s, 3H), 5.76 (s, 1H), 7.18-7.33 (m, 5H),7.33-7.40 (m, 2H), 7.45-7.55 (m, 1H), 10.41 (s, 1H).

Example 1-101

MS ESI m/e: 503 (M+H), 501 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.78-0.91 (m, 2H), 1.14-1.26 (m, 2H),2.73-2.86 (m, 1H), 2.82 (s, 3H), 5.76 (s, 1H), 7.19-7.29 (m, 2H),7.32-7.41 (m, 2H), 7.42-7.50 (m, 1H), 7.61-7.79 (m, 2H), 7.80-7.89 (m,1H), 10.50 (s, 1H).

Example 1-102

MS ESI m/e: 449 (M+H), 447 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.74-0.96 (m, 2H), 1.11-1.31 (m, 2H), 2.30 (s,3H), 2.74 (s, 3H), 2.76-2.85 (m, 1H), 5.76 (s, 1H), 7.04-7.12 (m, 1H),7.18-7.43 (m, 7H), 10.53 (s, 1H).

Example 1-103

MS ESI m/e: 463 (M+H), 461 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.76-0.90 (m, 2H), 1.11-1.27 (m, 2H), 1.26 (t,J=7.5 Hz, 3H), 2.40-2.67 (m, 2H), 2.71-2.84 (m, 1H), 2.75 (s, 3H), 5.76(s, 1H), 7.08-7.14 (m, 1H), 7.18-7.47 (m, 7H), 10.54 (s, 1H).

Example 1-104

MS ESI m/e: 465 (M+H), 463 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.79-0.94 (m, 2H), 1.11-1.28 (m, 2H),2.71-2.83 (m, 1H), 2.84 (s, 3H), 3.84 (s, 3H), 5.76 (s, 1H), 7.00-7.13(m, 2H), 7.19-7.30 (m, 3H), 7.32-7.40 (m, 2H), 7.41-7.52 (m, 1H), 10.52(s, 1H).

Example 1-105

MS ESI m/e: 445 (M+H), 443 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.92 (t, J=7.5 Hz, 3H), 1.36 (sext, J=7.5 Hz,2H), 1.59 (quint, J=7.5 Hz, 2H), 2.33 (s, 3H), 2.62 (t, J=7.5 Hz, 2H),2.75 (s, 3H), 3.45 (s, 3H), 5.43 (s, 1H), 7.08-7.45 (m, 8H), 10.37 (s,1H).

Example 1-106

MS ESI m/e: 458 (M+H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.77-0.92 (m, 2H), 1.14-1.27 (m, 2H), 2.30 (s,3H), 2.72 (s, 3H), 2.74-2.85 (m, 1H), 2.96 (s, 6H), 5.60 (s, 1H),6.69-6.79 (m, 2H), 7.03-7.18 (m, 3H), 7.22-7.42 (m, 3H), 10.20 (s, 1H).

Example 1-107

MS ESI m/e: 493, 495 (M+H), 491, 493 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.68-1.79 (m, 2H), 2.19-2.32 (m, 2H), 2.59(s, 3H), 2.60-2.75 (m, 2H), 4.88-4.98 (m, 1H), 5.49 (s, 1H), 7.29 (d,J=8.7 Hz, 2H), 7.41-7.53 (m, 5H), 7.60 (d, J=8.6 Hz, 2H), 10.52 (brs,1H).

Example 1-108

MS ESI m/e: 535, 537 (M+H), 533, 535 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.27 (s, 3H), 2.54 (s, 3H), 4.62-4.88 (m,2H), 5.49 (s, 1H), 7.28-7.30 (m, 4H), 7.41-7.42 (m, 2H), 7.62 (d, J=9.0Hz, 2H), 10.40 (brs, 1H).

Example 1-109

MS ESI m/e: 437 (M+H), 435 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 1.30 (t, J=6.0 Hz, 3H), 2.30 (s, 3H), 2.75 (s,3H), 4.09 (q, J=6.0 Hz, 2H), 5.75 (s, 1H), 7.12 (d, J=6.0 Hz, 1H),7.19-7.43 (m, 7H), 10.65 (s, 1H).

Example 1-110

MS ESI m/e: 446 (M+H), 444 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 1.30 (t, J=7.1 Hz, 3H), 2.30 (s, 3H), 2.73 (s,3H), 2.96 (s, 6H), 4.09 (q, J=2.3 Hz, 2H), 4.84 (q, J=149.0 Hz, 2H),6.68-6.77 (m, 2H), 7.08-7.17 (m, 3H), 7.25-7.32 (m, 1H), 7.33-7.38 (m,2H), 10.31 (brs, 1H).

Example 1-111

MS ESI m/e: 481, 483 (M+H), 479, 481 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 1.30 (t, J=6.0 Hz, 3H), 2.30 (s, 1H), 2.75 (s,1H), 4.09 (q, J=7.0 Hz, 2H), 5.77 (s, 1H), 7.08-7.22 (m, 3H), 7.26-7.42(m, 3H), 7.49-7.56 (m, 2H), 10.66 (brs, 1H).

Example 1-112

MS ESI m/e: 458 (M+H), 456 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.83-0.93 (m, 2H), 1.14-1.24 (m, 2H), 2.23 (s,3H), 2.71-2.82 (m, 1H), 2.79 (s, 3H), 2.95 (s, 6H), 5.29 (s, 1H),6.55-6.64 (m, 2H), 7.02-7.10 (m, 1H), 7.29-7.36 (m, 2H), 7.38-7.53 (m,3H), 9.86 (s, 1H).

Example 1-113

MS ESI m/e: 497, 499 (M+H), 495, 497 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.92 (m, 2H), 1.14-1.24 (m, 2H),2.73-2.83 (m, 1H), 2.86 (s, 3H), 5.78 (s, 1H), 7.12-7.21 (m, 2H),7.21-7.34 (m, 3H), 7.45-7.55 (m, 3H), 10.41 (s, 1H).

Example 1-114

MS ESI m/e: 462 (M+H), 460 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.83-0.93 (m, 2H), 1.13-1.25 (m, 2H),2.72-2.84 (m, 1H), 2.84 (s, 3H), 2.96 (s, 6H), 5.60 (s, 1H), 6.69-6.77(m, 2H), 7.08-7.15 (m, 2H), 7.17-7.31 (m, 3H), 7.43-7.53 (m, 1H), 10.09(s, 1H).

Example 1-115

MS ESI m/e: 441 (M+H), 439 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 1.31 (t, J=7.0 Hz, 3H), 2.86 (s, 3H), 4.08 (q,J=7.0 Hz, 2H), 5.75 (s, 1H), 7.18-7.40 (m, 7H), 7.46-7.56 (m, 1H), 10.54(s, 1H).

Example 1-116

MS ESI m/e: 485, 487 (M+H), 483, 485 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 1.31 (t, J=7.0 Hz, 3H), 2.86 (s, 3H), 4.08 (q,J=7.0 Hz, 2H), 5.77 (s, 1H), 7.13-7.21 (m, 2H), 7.24-7.34 (m, 3H),7.46-7.56 (m, 3H), 10.55 (s, 1H).

Example 1-117

MS ESI m/e: 450 (M+H), 448 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 1.31 (t, J=7.0 Hz, 3H), 2.85 (s, 3H), 2.96 (s,6H), 4.08 (q, J=7.1 Hz, 2H), 5.59 (s, 1H), 6.69-6.77 (m, 2H), 7.08-7.17(m, 2H), 7.22-7.34 (m, 3H), 7.43-7.54 (m, 1H), 10.21 (s, 1H).

Example 1-118

MS ESI m/e: 472 (M+H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.79-0.89 (m, 2H), 1.14-1.25 (m, 2H), 2.16 (s,6H), 2.71 (s, 3H), 2.77-2.87 (m, 1H), 2.96 (s, 6H), 5.59 (s, 1H),6.68-6.77 (m, 2H), 7.08-7.19 (m, 4H), 7.23-7.31 (m, 1H), 10.31 (s, 1H).

Example 1-119

MS ESI m/e: 480 (M+H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 0.99-1.10 (m, 2H),2.68-2.79 (m, 1H), 2.71 (s, 1H), 5.21 (s, 1H), 6.79 (d, J=9.0 Hz, 2H),7.12 (d, J=9.0 Hz, 2H), 7.39 (t, J=9.0 Hz, 2H), 7.65-7.75 (m, 1H), 10.11(brs, 1H).

Example 1-120

MS ESI m/e: 515, 517 (M+H), 513, 515 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 1.00-1.10 (m, 2H),2.71-2.80 (m, 1H), 2.74 (s, 3H), 5.51 (s, 1H), 7.32 (d, J=9.0 Hz, 2H),7.41 (t, J=7.5 Hz, 2H), 7.62 (d, J=6.0 Hz, 2H), 7.64-7.76 (m, 1H), 10.47(brs, 1H).

Example 1-121

MS ESI m/e: 471 (M+H), 469 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 1.03-1.07 (m, 2H),2.70-2.80 (m, 1H), 2.74 (s, 3H), 5.49 (s, 1H), 7.36-7.43 (m, 4H), 7.50(d, J=9.0 Hz, 2H), 7.65-7.76 (m, 1H), 10.47 (brs, 1H).

Example 1-122

MS ESI m/e: 460 (M+H), 458 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.16 (t, J=7.5 Hz, 3H), 1.18 (t, J=6.0 Hz,3H), 2.52 (q, J=4.0 Hz, 2H), 2.50 (s, 3H), 2.92 (s, 6H), 3.94 (q, J=5.0Hz, 2H), 5.20 (s, 1H), 6.79 (d, J=9.0 Hz, 2H), 7.12 (d, J=9.0 Hz, 2H),7.33 (d, J=3.0 Hz, 2H), 7.47 (s, 2H), 10.35 (brs, 1H).

Example 1-123

MS ESI m/e: 495, 497 (M+H), 493, 495 (M−H).

¹H-NMR (DMSO-d, 300 MHz) δ 1.16 (t, J=7.5 Hz, 3H), 1.18 (t, J=6.0 Hz,3H), 2.50-2.56 (m, 2H), 2.53 (s, 3H), 3.96 (q, J=7.0 Hz, 2H), 5.51 (s,1H), 7.29-7.34 (m, 4H), 7.46-7.48 (m, 2H), 7.62 (d, J=6.0 Hz, 2H), 10.74(brs, 1H).

Example 1-124

MS ESI m/e: 451 (M+H), 499 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.16 (t, J=6.0 Hz, 3H), 1.18 (t, J=6.0 Hz,3H), 2.50-2.55 (m, 2H), 2.56 (s, 3H), 3.95 (q, J=8.0 Hz, 2H), 5.49 (s,1H), 7.33-7.38 (m, 4H), 7.48-7.51 (m, 4H), 10.73 (brs, 1H).

Example 1-125

MS ESI m/e: 463 (M+H), 461 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.78-0.88 (m, 2H), 1.16-1.29 (m, 2H), 2.15 (s,6H), 2.72 (s, 3H), 2.77-2.88 (m, 1H), 5.74 (s, 1H), 7.11-7.40 (m, 7H),10.64 (s, 1H).

Example 1-126

MS ESI m/e: 458 (M+H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.83-0.90 (m, 2H), 1.13-1.23 (m, 2H), 2.39 (s,3H), 2.71-2.78 (m, 1H), 2.81 (s, 3H), 2.96 (s, 6H), 5.60 (s, 1H),6.68-6.78 (m, 2H), 7.07-7.32 (m, 6H), 10.08 (brs, 1H).

Example 1-127

MS ESI m/e: 458 (M+H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.93 (m, 2H), 1.13-1.23 (m, 2H), 2.39 (s,3H), 2.71-2.81 (m, 1H), 2.83 (s, 3H), 2.96 (s, 6H), 5.62 (s, 1H),6.70-6.76 (m, 2H), 7.08-7.16 (m, 4H), 7.20-7.25 (m, 1H), 7.31-7.39 (m,1H), 10.08 (brs, 1H).

Example 1-128

MS ESI m/e: 472 (M+H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.92 (m, 2H), 1.14-1.25 (m, 2H), 1.18 (t,J=7.0 Hz, 6H), 2.71-2.82 (m, 1H), 2.80 (s, 3H), 3.36 (q, J=7.0 Hz, 4H),5.62 (s, 1H), 6.63-6.71 (m, 2H), 7.03-7.13 (m, 2H), 7.28-7.36 (m, 2H),7.37-7.53 (m, 3H), 10.03 (s, 1H).

Example 1-129

MS ESI m/e: 431 (M+H), 429 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.84-0.90 (m, 2H), 1.15-1.23 (m, 2H),2.72-2.80 (m, 1H), 2.80 (s, 3H), 3.82 (s, 3H), 5.61 (s, 1H), 6.88-6.94(m, 2H), 7.14-7.21 (m, 2H), 7.28-7.33 (m, 2H), 7.38-7.50 (m, 3H), 10.15(s, 1H).

Example 1-130

MS ESI m/e: 408 (M+H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.68-0.73 (m, 4H), 0.96-1.02 (m, 2H),1.05-1.12 (m, 2H), 2.54-2.63 (m, 1H), 2.91 (s, 6H), 3.30-3.40 (m, 1H),3.48 (s, 3H), 5.14 (s, 1H), 6.77 (d, J=9.0 Hz, 2H), 7.06 (d, J=9.0 Hz,2H), 10.04 (brs, 1H).

Example 1-131

MS ESI m/e: 468, 470 (M+H), 466, 468 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.20 (t, J=7.5 Hz, 3H), 2.62 (s, 3H), 3.95(q, J=7.0 Hz, 2H), 5.53 (s, 1H), 7.32 (d, J=9.0 Hz, 2H), 7.52-7.64 (m,3H), 7.97 (d, J=9.0 Hz, 1H), 8.67 (d, J=15 Hz, 1H), 8.68 (d, J=15 Hz,1H), 10.62 (brs, 1H).

Example 1-132

MS ESI m/e: 462 (M+H), 460 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.82-0.89 (m, 2H), 1.15-1.22 (m, 2H),2.72-2.79 (m, 1H), 2.82 (s, 3H), 2.96 (s, 6H), 5.60 (s, 1H), 6.69-6.75(m, 2H), 7.07-7.21 (m, 4H), 7.27-7.33 (m, 2H), 10.03 (s, 1H).

Example 1-133

MS ESI m/e: 462 (M+H), 460 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.83-0.89 (m, 2H), 1.15-1.23 (m, 2H),2.72-2.80 (m, 1H), 2.85 (s, 3H), 2.96 (s, 6H), 5.61 (s, 1H), 6.69-6.75(m, 2H), 7.03-7.19 (m, 5H), 7.39-7.46 (m, 1H), 10.01 (s, 1H).

Example 1-134

MS ESI m/e: 444 (M+H), 442 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.93 (m, 2H), 1.13-1.24 (m, 2H),2.72-2.82 (m, 1H), 2.82 (s, 3H), 2.96 (s, 6H), 5.90 (s, 1H), 6.55-6.62(m, 2H), 6.63-6.69 (m, 1H), 7.19-7.24 (m, 1H), 7.30-7.35 (m, 2H),7.38-7.53 (m, 3H), 10.31 (s, 1H).

Example 1-135

MS ESI m/e: 416 (M+H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.82 (m, 2H), 0.99-1.09 (m, 2H), 2.60(s, 3H), 2.63-2.74 (m, 1H), 5.52 (s, 1H), 7.36-7.57 (m, 9H), 10.61 (s,1H).

Example 1-136

MS ESI m/e: 430 (M+H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.80 (m, 2H), 0.98-1.08 (m, 2H), 2.60(s, 3H), 2.63-2.72 (m, 1H), 2.89 (s, 3H), 5.51 (d, J=2.9 Hz, 1H),7.38-7.56 (m, 9H), 10.59 (brs, 1H).

Example 1-137

MS ESI m/e: 444 (M+H), 442 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.80 (m, 2H), 0.98-1.08 (m, 2H), 1.27(t, J=7.5 Hz, 3H), 2.61 (s, 3H), 2.64-2.72 (m, 1H), 3.31 (q, J=7.0 Hz,2H), 5.54 (s, 1H), 7.07-7.19 (m, 2H), 7.38-7.57 (m, 9H), 10.62 (brs,1H).

Example 1-138

MS ESI m/e: 454 (M+H).

¹H-NMR (DMSO-ds, 300 MHz) δ 0.71-0.80 (m, 2H), 0.99-1.08 (m, 2H), 2.57(s, 3H), 2.62-2.75 (m, 1H), 3.81 (s, 3H), 5.26 (s, 1H), 6.44 (d, J=3.0Hz, 1H), 7.06 (dd, J=3.0, 3.0 Hz, 1H), 7.37-7.52 (m, 8H), 10.37 (brs,1H).

Example 1-139

MS ESI m/e: 444 (M+H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.59 (s, 3H), 2.92 (s, 6H), 4.49 (d, J=3.0Hz, 2H), 5.15 (d, J=9.0 Hz, 1H), 5.22 (dd, J=3.0, 9.0 Hz, 2H), 6.78 (d,J=6.0 Hz, 2H), 7.10 (d, J=6.0 Hz, 2H), 7.48-7.50 (m, 5H), 10.19 (brs,1H).

Example 1-140

MS ESI m/e: 444 (M+H), 442 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.60 (s, 3H), 3.03 (s, 6H), 4.50 (d, J=3.0Hz, 2H), 5.17 (dd, J=21.0, 24.0 Hz, 2H), 5.38 (s, 1H), 5.79-5.92 (m,1H), 7.19-7.38 (m, 4H), 7.41-7.55 (m, 5H), 10.42 (brs, 1H).

Example 1-141

MS ESI m/e: 456 (M+H), 454 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.79 (m, 2H), 0.99-1.08 (m, 2H), 2.55(s, 3H), 2.61-2.68 (m, 1H), 2.71 (s, 3H), 2.89 (t, J=9.0 Hz, 2H), 3.28(t, J=7.5 Hz, 2H), 5.18 (s, 1H), 6.54 (d, J=9.0 Hz, 1H), 6.90 (d, J=6.0Hz, 1H), 6.96 (s, 1H), 7.39-7.50 (m, 5H), 10.13 (brs, 1H).

Example 1-142

MS ESI m/e: 476 (M+H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.85-0.93 (m, 2H), 1.14-1.24 (m, 2H), 2.23 (s,3H), 2.74-2.83 (m, 1H), 2.83 (s, 3H), 2.95 (s, 6H), 5.27 (s, 1H),6.55-6.65 (m, 2H), 7.02-7.09 (m, 1H), 7.18-7.32 (m, 3H), 7.43-7.54 (m,1H), 9.89 (s, 1H).

Example 1-143

MS ESI m/e: 462 (M+H), 460 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.92 (m, 2H), 1.14-1.25 (m, 2H),2.71-2.81 (m, 1H), 2.81 (s, 1H), 2.87 (s, 6H), 5.71 (s, 1H), 6.86-7.02(m, 3H), 7.27-7.35 (m, 2H), 7.41-7.54 (m, 3H), 10.22 (brs, 1H).

Example 1-144

MS ESI m/e: 454 (M+H), 452 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.80 (m, 2H), 1.00-1.09 (m, 2H), 2.58(s, 3H), 2.64-2.71 (m, 11-H), 3.78 (s, 3H), 5.40 (s, 1H), 6.45 (d, J=3.0Hz, 1H), 6.97 (d, J=6.0 Hz, 1H), 7.34-7.51 (m, 7H), 7.60 (d, J=9.0 Hz,1H), 8.30 (brs, 1H).

Example 1-145

MS ESI m/e: 479 (M+H), 477 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.91 (m, 2H), 1.15-1.26 (m, 2H),2.73-2.83 (m, 1H), 2.85 (s, 3H), 3.08 (s, 3H), 6.08 (s, 1H), 7.29-7.37(m, 2H), 7.41-7.56 (m, 5H), 7.92-8.00 (m, 2H), 10.87 (s, 1H).

Example 1-146

MS ESI m/e: 461 (M+H), 459 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.92 (m, 2H), 1.13-1.24 (m, 2H),2.72-2.83 (m, 1H), 2.80 (s, 3H), 3.83 (s, 3H), 3.84 (s, 3H), 5.60 (s,1H), 6.45-6.58 (m, 2H), 7.19-7.26 (m, 1H), 7.28-7.35 (m, 2H), 7.38-7.52(m, 3H), 10.01 (s, 1H).

Example 1-147

MS ESI m/e: 458 (M+H), 456 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.91 (m, 2H), 1.13-1.23 (m, 2H), 2.32 (s,3H), 2.67-2.84 (m, 1H), 2.71 (s, 6H), 2.81 (s, 3H), 5.72 (s, 1H),6.99-7.10 (m, 3H), 7.28-7.36 (m, 2H), 7.38-7.53 (m, 3H), 10.19 (s, 1H).

Example 1-148

MS ESI m/e: 512 (M+H), 510 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.84-0.90 (m, 2H), 1.16-1.24 (m, 2H),2.73-2.79 (m, 1H), 2.75 (s, 6H), 2.81 (s, 3H), 5.66 (s, 1H), 7.29-7.37(m, 3H), 7.39-7.52 (m, 5H), 10.33 (brs, 1H).

Example 1-149

MS ESI m/e: 472 (M+H), 470 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.84-0.91 (m, 2H), 1.17-1.25 (m, 2H), 1.91 (s,3H), 2.74-2.81 (m, 1H), 2.83 (s, 3H), 3.28 (s, 3H), 5.84 (s, 1H),7.18-7.24 (m, 2H), 7.29-7.35 (m, 4H), 7.40-7.52 (m, 3H), 10.47 (s, 1H).

Example 1-150

MS ESI m/e: 493, 495 (M+H), 491, 493 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.39-0.57 (m, 4H), 1.24-1.36 (m, 1H), 2.83 (s,3H), 3.91 (d, J=7.0 Hz, 2H), 5.80 (s, 1H), 7.15-7.21 (m, 2H), 7.33-7.39(m, 2H), 7.42-7.55 (m, 5H), 10.57 (s, 1H).

Example 1-151

MS ESI m/e: 497, 499 (M+H), 495, 497 (M−H).

¹H-NMR (DMSO-ds, 300 MHz) δ 0.73-0.79 (m, 2H), 1.01-1.09 (m, 2H), 2.61(s, 3H), 2.68-2.71 (m, 1H), 5.65 (s, 1H), 7.19 (d, J=9.0 Hz, 1H),7.40-7.52 (m, 6H), 7.73 (t, J=9.0 Hz, 1H), 10.67 (brs, 1H).

Example 1-152

MS ESI m/e: 497, 499 (M+H), 495, 497 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.79 (m, 2H), 1.01-1.09 (m, 2H), 2.60(s, 3H), 2.62-2.72 (m, 1H), 5.37 (s, 1H), 7.42-7.52 (m, 7H), 7.73 (d,J=12.0 Hz, 1H), 10.55 (brs, 1H).

Example 1-153

MS ESI m/e: 493, 495 (M+H), 491, 493 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.81-1.17 (m, 6H), 2.29-2.35 (m, 1H), 2.58(s, 3H), 5.50 (s, 1H), 7.29 (d, J=6.0 Hz, 2H), 7.39-7.52 (m, 5H), 7.61(d, J=9.0 Hz, 2H), 10.56 (brs, 1H).

Example 1-154

MS ESI m/e: 445 (M+H), 443 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.84-0.93 (m, 2H), 1.16-1.24 (m, 2H), 2.26 (s,3H), 2.74-2.80 (m, 1H), 2.80 (s, 3H), 3.81 (s, 3H), 5.27 (s, 1H),6.73-6.84 (m, 2H), 7.14 (d, J=9.0 Hz, 1H), 7.30-7.35 (m, 2H), 7.39-7.52(m, 3H), 9.94 (brs, 1H).

Example 1-155

MS ESI m/e: 444 (M+H), 442 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 1.00-1.10 (m, 2H), 2.60(s, 3H), 2.64-2.76 (m, 1H), 2.76 (brs, 6H), 5.51 (brs, 1H), 7.09-7.58(m, 8H), 10.46 (brs, 1H).

Example 1-156

MS ESI m/e: 493, 495 (M+H), 491, 495 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.92 (m, 2H), 1.15-1.25 (m, 2H), 2.29 (s,3H), 2.73-2.85 (m, 1H), 2.81 (s, 3H), 5.41 (s, 1H), 7.16 (d, J=8.4 Hz,1H), 7.30-7.39 (m, 3H), 7.40-7.53 (m, 4H), 10.13 (s, 1H).

Example 1-157

MS ESI m/e: 493, 495 (M+H), 491, 495 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.91 (m, 2H), 1.14-1.24 (m, 2H), 2.40 (s,3H), 2.71-2.82 (m, 1H), 2.82 (s, 3H), 5.81 (s, 1H), 6.99 (dd, J=2.6, 8.4Hz, 1H), 7.17 (d, J=2.6 Hz, 1H), 7.28-7.36 (m, 2H), 7.39-7.57 (m, 4H),10.37 (s, 1H).

Example 1-158

MS ESI m/e: 454 (M+H), 452 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.80 (m, 2H), 1.01-1.09 (m, 2H), 2.55(s, 3H), 2.63-2.72 (m, 1H), 3.85 (s, 3H), 4.71 (s, 1H), 6.48 (d, J=3.0Hz, 1H), 6.97 (d, J=15.0 Hz, 1H), 7.06 (t, J=9.0 Hz, 1H), 7.29 (d, J=3.0Hz, 1H), 7.41-7.56 (m, 6H), 10.37 (brs, 1H).

Example 1-159

MS ESI m/e: 509, 511 (M+H), 507, 509 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.61-0.79 (m, 2H), 0.96-1.08 (m, 2H), 2.61(s, 3H), 2.61-2.74 (m, 1H), 3.77 (s, 3H), 5.49 (s, 1H), 7.07 (t, J=6.0Hz, 1H), 7.20 (d, J=12.0 Hz, 1H), 7.29 (d, J=9.0 Hz, 2H), 7.38 (d, J=6.0Hz, 1H), 7.48 (t, J=9.0 Hz, 1H), 7.60 (d, J=9.0 Hz, 2H), 10.60 (brs,1H).

Example 1-160

MS ESI m/e: 455 (M+H), 453 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.85-0.93 (m, 2H), 1.15-1.26 (m, 2H),2.74-2.84 (m, 1H), 2.81 (s, 3H), 3.88 (s, 3H), 5.65 (s, 1H), 7.22-7.29(m, 1H), 7.30-7.37 (m, 2H), 7.37-7.54 (m, 4H), 7.70 (d, J=1.8 Hz, 1H),7.90 (s, 1H), 10.36 (s, 1H).

Example 1-161

MS ESI m/e: 455 (M+H), 453 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.85-0.94 (m, 2H), 1.15-1.26 (m, 2H),2.74-2.84 (m, 1H), 2.82 (s, 3H), 4.10 (s, 3H), 5.65 (s, 1H), 7.28-7.37(m, 3H), 7.39-7.54 (m, 4H), 7.60-7.64 (m, 1H), 7.95-7.98 (m, 1H), 10.36(s, 1H).

Example 1-162

MS ESI m/e: 437 (M+H), 435 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.83-0.91 (m, 2H), 1.15-1.24 (m, 2H),2.73-2.81 (m, 1H), 2.81 (s, 3H), 5.49 (s, 1H), 6.88-6.98 (m, 2H),7.28-7.38 (m, 3H), 7.39-7.52 (m, 3H), 10.15 (s, 1H).

Example 1-163

MS ESI m/e: 469, 471 (M+H), 467, 469 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.83-0.90 (m, 2H), 1.16-1.24 (m, 2H),2.74-2.81 (m, 1H), 2.82 (s, 3H), 5.70 (s, 1H), 7.24-7.34 (m, 3H),7.39-7.52 (m, 5H), 10.50 (s, 1H).

Example 1-164

MS ESI m/e: 485, 487 (M+H), 483, 485 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 1.30 (t, J=7.1 Hz, 3H), 2.82 (s, 3H), 4.08 (q,J=7.0 Hz, 2H), 5.66 (s, 1H), 7.28-7.39 (m, 5H), 7.41-7.53 (m, 3H), 10.48(s, 1H).

Example 1-165

MS ESI m/e: 440 (M+H), 438 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.81 (m, 2H), 1.00-1.10 (m, 2H), 2.58(s, 3H), 2.62-2.78 (m, 1H), 5.28 (s, 1H), 6.46 (s, 1H), 7.01 (d, J=9.0Hz, 1H), 7.40-7.68 (m, 8H), 10.37 (brs, 1H), 11.22 (brs, 1H).

Example 1-166

MS ESI m/e: 527, 529 (M+H), 525, 527 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.81 (m, 2H), 0.99-1.09 (m, 2H), 2.63(s, 3H), 2.66-2.75 (m, 1H), 3.79 (s, 3H), 5.34 (s, 1H), 7.09 (t, J=7.5Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 7.40 (d, J=6.0 Hz, 1H), 7.43-7.54 (m,3H), 7.73 (d, J=9.0 Hz, 1H), 10.58 (brs, 1H).

Example 1-167

MS ESI m/e: 468 (M+H), 466 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.94 (m, 2H), 1.14-1.26 (m, 2H), 1.49 (t,J=7.4 Hz, 3H), 2.72-2.84 (m, 1H), 2.81 (s, 3H), 4.19 (q, J=7.3 Hz, 2H),5.68 (s, 1H), 6.47 (d, J=3.0 Hz, 1H), 7.10 (dd, J=1.9, 8.6 Hz, 1H), 7.16(d, J=3.0 Hz, 1H), 7.29-7.38 (m, 3H), 7.38-7.55 (m, 4H), 10.27 (brs,1H).

Example 1-168

MS ESI m/e: 433 (M+H), 431 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.75-0.90 (m, 2H), 1.10-1.25 (m, 2H), 2.37 (s,3H), 2.77 (m, 1H), 2.81 (s, 3H), 5.59 (s, 1H), 6.90-7.05 (m, 2H), 7.25(t, J=8.3 Hz, 1H), 7.30-7.35 (m, 2H), 7.40-7.50 (m, 3H), 10.16 (s, 1H).

Example 1-169

MS ESI m/e: 438 (M+H), 436 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.75-0.85 (m, 2H), 1.10-1.25 (m, 2H),2.50-2.55 (m, 4H), 2.65-2.80 (m, 3H), 2.80 (s, 3H), 3.26 (q, J=5.8 Hz,2H), 3.70-3.80 (m, 4H), 5.37 (s, 1H), 7.25-7.35 (m, 2H), 7.35-7.50 (m,3H), 8.90 (brs, 1H).

Example 1-170

MS ESI m/e: 477 (M+H), 475 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.92 (m, 2H), 1.15-1.26 (m, 2H), 1.76 (d,J=12.8 Hz, 6H), 2.72-2.82 (m, 1H), 2.84 (s, 3H), 5.99 (s, 1H), 7.29-7.36(m, 2H), 7.39-7.56 (m, 5H), 7.70-7.82 (m, 2H), 10.67 (s, 1H).

Example 1-171

MS ESI m/e: 453 (M+H), 451 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.68-0.79 (m, 2H), 0.98-1.09 (m, 2H), 2.58(s, 3H), 2.61-2.71 (m, 1H), 5.32 (s, 1H), 7.34-7.63 (m, 8H), 10.52 (brs,1H).

Example 1-172

MS ESI m/e: 417 (M+H), 415 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.68-0.78 (m, 2H), 0.97-1.06 (m, 2H), 2.55(s, 3H), 2.61-2.69 (m, 1H), 5.19 (s, 1H), 6.82 (d, J=9.0 Hz, 2H), 7.08(d, J=6.0 Hz, 2H), 7.39-7.50 (m, 5H), 9.53 (brs, 1H), 10.18 (brs, 1H).

Example 1-173

MS ESI m/e: 419 (M+H), 417 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.71-2.80 (m, 2H), 1.01-1.09 (m, 2H), 2.60(s, 3H), 2.64-2.72 (m, 1H), 5.34 (s, 1H), 7.28-7.54 (m, 9H), 10.53 (brs,1H).

Example 1-174

MS ESI m/e: 437 (M+H), 435 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.78 (m, 2H), 0.96-1.08 (m, 2H), 2.57(s, 3H), 2.61-2.72 (m, 1H), 4.84 (s, 1H), 7.24-7.52 (m, 8H), 10.15 (brs,1H).

Example 1-175

MS ESI m/e: 449 (M+H), 447 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.83-0.92 (m, 2H), 1.15-1.24 (m, 2H),2.72-2.81 (m, 1H), 2.81 (s, 3H), 3.82 (s, 3H), 5.46 (d, J=1.6 Hz, 1H),6.69-6.79 (m, 2H), 7.19-7.29 (m, 1H), 7.29-7.36 (m, 2H), 7.39-7.54 (m,3H), 10.01 (brs, 1H).

Example 1-176

MS ESI m/e: 513, 515 (M+H), 511, 513 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.83-0.91 (m, 2H), 1.16-1.24 (m, 2H),2.75-2.82 (m, 1H), 2.82 (s, 3H), 5.73 (s, 1H), 7.30-7.36 (m, 2H),7.38-7.53 (m, 4H), 7.41 (d, J=1.8 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 10.53(brs, 1H).

Example 1-177

MS ESI m/e: 507, 509 (M+H), 505, 507 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.85-0.89 (m, 2H), 1.17-1.22 (m, 2H), 1.23 (t,J=7.5 Hz, 3H), 2.63 (q, J=7.5 Hz, 2H), 2.74-2.79 (m, 1H), 2.80 (s, 3H),5.40 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.29-7.36 (m, 3H), 7.40-7.51 (m,4H), 10.11 (brs, 1H).

Example 1-178

MS ESI m/e: 459 (M+H), 457 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.79 (m, 2H), 1.00-1.09 (m, 2H), 2.63(s, 3H), 2.65-2.72 (m, 1H), 3.86 (s, 3H), 5.84 (s, 1H), 7.42-7.56 (m,6H), 7.99-8.03 (m, 2H), 10.96 (brs, 1H).

Example 1-179

MS ESI m/e: 383 (M+H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.79-0.87 (m, 2H), 1.12-1.21 (m, 2H),2.69-2.76 (m, 1H), 2.80 (s, 3H), 3.36 (q, J=5.4 Hz, 2H), 3.44 (s, 3H),3.66 (t, J=5.4 Hz, 2H), 5.39 (s, 1H), 7.23-7.31 (m, 2H), 7.37-7.51 (m,3H), 8.80-8.88 (m, 1H).

Example 1-180

MS ESI m/e: 422 (M+H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.65-0.74 (m, 2H), 0.95-1.05 (m, 2H),1.42-1.56 (m, 2H), 1.88-1.98 (m, 2H), 2.10-2.21 (m, 2H), 2.18 (s, 3H),2.55 (s, 3H), 2.58-2.70 (m, 3H), 3.33-3.44 (m, 1H), 5.23 (s, 1H),7.34-7.41 (m, 2H), 7.42-7.53 (m, 3H), 8.77-8.84 (m, 1H).

Example 1-181

MS ESI m/e: 365 (M+H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.59-0.67 (m, 2H), 0.77-0.89 (m, 4H),1.11-1.21 (m, 2H), 2.42-2.50 (m, 1H), 2.66-2.76 (m, 1H), 2.81 (s, 3H),5.81 (s, 1H), 7.24-7.28 (m, 1H), 7.29-7.31 (m, 1H), 7.37-7.51 (m, 3H),8.68 (brs, 1H).

Example 1-182

MS ESI m/e: 450 (M+H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.77-0.86 (m, 2H), 1.01-1.12 (m, 6H),1.12-1.21 (m, 2H), 1.54-1.74 (m, 2H), 2.03-2.15 (m, 2H), 2.25-2.41 (m,2H), 2.66-2.76 (m, 1H), 2.79 (s, 3H), 2.82-2.94 (m, 2H), 3.25-3.41 (m,1H), 5.40 (s, 1H), 7.25-7.28 (m, 1H), 7.29-7.32 (m, 1H), 7.37-7.51 (m,3H), 8.71-8.79 (m, 1H).

Example 1-183

MS ESI m/e: 509, 511 (M+H), 507, 509 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.90 (m, 2H), 1.13-1.24 (m, 2H),2.71-2.81 (m, 2H), 2.85 (s, 3H), 3.84 (s, 3H), 5.78 (s, 1H), 6.93-7.00(m, 2H), 7.13-7.19 (m, 2H), 7.19-7.23 (m, 2H), 7.47-7.53 (m, 2H), 10.42(brs, 1H).

Example 1-184

MS ESI m/e: 410 (M+H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.75-0.88 (m, 2H), 1.09-1.22 (m, 2H), 1.85(tt, J=7.0, 14.0 Hz, 2H), 2.26 (s, 6H), 2.40 (t, J=7.1 Hz, 2H),2.67-2.77 (m, 1H), 2.79 (s, 3H), 3.22 (dt, J=5.5, 6.2 Hz, 3H), 5.40 (s,1H), 7.25-7.33 (m, 2H), 7.37-7.52 (m, 3H), 8.74 (t, J=4.8 Hz, 1H).

Example 1-185

MS ESI m/e: 471, 473 (M+H), 469, 471 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.62 (s, 3H), 3.27 (s, 3H), 5.37 (s, 1H),7.40-7.60 (m, 7H), 7.70-7.80 (m, 1H), 10.61 (s, 1H).

Example 1-186

MS ESI m/e: 527, 529 (M+H), 525, 527 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.90 (m, 2H), 1.13-1.24 (m, 2H),2.71-2.82 (m, 1H), 2.85 (s, 3H), 3.84 (s, 3H), 5.64 (d, J=1.1 Hz, 1H),6.94-7.01 (m, 2H), 7.17-7.24 (m, 2H), 7.29-7.33 (m, 2H), 7.34-7.40 (m,1H), 10.35 (brs, 1H).

Example 1-187

MS ESI m/e: 459 (M+H), 457 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.92 (m, 2H), 1.13-1.24 (m, 2H), 1.35 (d,J=6.0 Hz, 6H), 2.72-2.82 (m, 1H), 2.81 (s, 3H), 4.54 (sept, J=6.0 Hz,1H), 5.63 (s, 1H), 6.85-6.94 (m, 2H), 7.12-7.20 (m, 2H), 7.29-7.35 (m,2H), 7.38-7.53 (m, 3H), 10.15 (brs, 1H).

Example 1-188

MS ESI m/e: 513, 515 (M+H), 511, 513 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.79 (m, 2H), 0.99-1.08 (m, 2H),2.62-2.72 (m, 1H), 2.66 (s, 3H), 5.35 (d, J=1.1 Hz, 1H), 6.79-6.89 (m,2H), 7.15-7.23 (m, 2H), 7.43-7.55 (m, 2H), 7.70-7.76 (m, 1H), 9.90 (brs,1H), 10.57 (brs, 1H).

Example 1-189

MS ESI m/e: 509, 511 (M+H), 507, 509 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.90 (m, 2H), 1.14-1.25 (m, 2H),2.73-2.80 (m, 1H), 2.82 (s, 3H), 3.89 (s, 3H), 5.80 (s, 1H), 7.07-7.13(m, 2H), 7.23-7.35 (m, 3H), 7.39-7.53 (m, 3H), 10.29 (brs, 1H).

Example 1-190

MS ESI m/e: 509, 511 (M+H), 507, 509 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 0.99-1.08 (m, 2H), 2.67(s, 3H), 2.66-2.68 (m, 1H), 3.78 (s, 3H), 5.53 (s, 1H), 6.97-7.06 (m,3H), 7.31 (d, J=9.0 Hz, 2H), 7.41 (dd, J=9.0, 9.0 Hz, 1H), 7.62 (d,J=9.0 Hz, 2H), 10.58 (brs, 1H).

Example 1-191

MS ESI m/e: 527, 529 (M+H), 525, 527 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 1.01-1.09 (m, 2H), 2.67(s, 3H), 2.66-2.67 (m, 1H), 3.78 (s, 3H), 5.37 (s, 1H), 6.97-7.06 (m,3H), 7.39-7.51 (m, 3H), 7.73 (d, J=12.0 Hz, 1H), 10.55 (brs, 1H).

Example 1-192

MS ESI m/e: 462 (M+H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 0.99-1.08 (m, 2H), 2.55(s, 3H), 2.60-2.71 (m, 1H), 2.92 (s, 6H), 5.01 (s, 1H), 6.56-6.66 (m,2H), 7.18 (dd, J=12.0, 9.0 Hz, 1H), 7.39-7.51 (m, 5H), 10.00 (brs, 1H).

Example 1-193

MS ESI m/e: 582, 584 (M+H), 580, 582 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75 (m, 2H), 1.03 (m, 2H), 2.60-2.75 (m,1H), 2.69 (s, 3H), 3.11 (brs, 4H), 3.73 (brs, 4H), 5.38 (s, 1H), 6.85(d, J=7.6 Hz, 1H), 7.02 (brs, 2H), 7.34 (t, J=8.5 Hz, 1H), 7.40-7.55 (m,2H), 7.73 (d, J=11.1 Hz, 1H), 10.57 (s, 1H).

Example 1-194

MS ESI m/e: 493, 495 (M+H), 491, 493 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.80-0.89 (m, 2H), 1.12-1.23 (m, 2H),2.68-2.80 (m, 1H), 2.79 (s, 3H), 4.37 (d, J=6.0 Hz, 2H), 5.33 (s, 1H),7.18-7.33 (m, 4H), 7.39-7.52 (m, 5H), 9.14 (t, J=5.6 Hz, 1H).

Example 1-195

MS ESI m/e: 493, 495 (M+H), 491, 493 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.79-0.89 (m, 2H), 1.12-1.22 (m, 2H),2.68-2.76 (m, 1H), 2.78 (s, 3H), 4.34 (d, J=5.6 Hz, 2H), 5.34 (s, 1H),7.20-7.31 (m, 4H), 7.39-7.53 (m, 5H), 9.11 (t, J=5.3 Hz, 1H).

Example 1-196

MS ESI m/e: 493, 495 (M+H), 491, 493 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.79-0.89 (m, 2H), 1.12-1.22 (m, 2H),2.69-2.77 (m, 1H), 2.79 (s, 3H), 4.46 (d, J=5.6 Hz, 2H), 5.36 (s, 1H),7.17 (dt, J=1.9, 7.5 Hz, 1H), 7.24-7.33 (m, 3H), 7.35 (dt, J=1.1, 7.7Hz, 1H), 7.39-7.51 (m, 3H), 7.59 (dd, J=1.1, 7.9 Hz, 1H), 9.16 (t, J=5.7Hz, 1H).

Example 1-197

MS ESI m/e: 445 (M+H), 443 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.83-0.92 (m, 2H), 1.14-1.25 (m, 2H),2.72-2.83 (m, 1H), 2.80 (s, 3H), 3.11 (s, 6H), 5.44 (s, 1H), 6.53 (d,J=9.0 Hz, 1H), 7.29-7.34 (m, 2H), 7.37 (dd, J=2.6, 9.0 Hz, 1H),7.39-7.52 (m, 3H), 8.07 (d, J=2.6 Hz, 1H), 9.96 (brs, 1H).

Example 1-198

MS EST m/e: 495, 497 (M+H), 493, 495 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.78 (m, 2H), 0.98-1.08 (m, 2H), 2.59(s, 3H), 2.61-2.72 (m, 1H), 5.50 (s, 1H), 7.04 (dd, J=2.3, 8.3 Hz, 1H),7.13 (d, J=2.3 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.38-7.55 (m, 5H), 10.45(s, 1H), 10.48 (brs, 1H).

Example 1-199

MS ESI m/e: 540, 542 (M+H), 538, 540 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.91 (m, 2H), 1.14-1.23 (m, 2H),2.71-2.82 (m, 1H), 2.93 (s, 3H), 2.96 (s, 6H), 5.66 (s, 1H), 6.52 (t,J=2.1 Hz, 1H), 6.59 (dd, J=1.9, 8.3 Hz, 1H), 6.71 (dd, J=2.6, 8.6 Hz,1H), 7.26-7.40 (m, 4H), 10.39 (brs, 1H).

Example 1-200

MS ESI m/e: 487, 489 (M+H), 485, 487 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.62 (s, 3H), 3.27 (s, 3H), 5.47 (s, 1H),7.40-7.60 (m, 6H), 7.63 (dd, J=2.1, 8.6 Hz, 1H), 7.91 (d, J=2.1 Hz, 1H),10.83 (s, 1H).

Example 1-201

MS ESI m/e: 569, 571 (M+H), 567, 569 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75 (m, 2H), 1.03 (m, 2H), 2.45-2.60 (m,2H), 2.60 (s, 3H), 2.67 (m, 1H), 2.85 (t, J=7.4 Hz, 2H), 5.36 (s, 1H),7.24 (d, J=7.9 Hz, 1H), 7.32 (brs, 2H), 7.41 (t, J=7.9 Hz, 1H),7.45-7.55 (m, 2H), 7.73 (d, J=9.2 Hz, 1H), 10.54 (s, 1H), 12.15 (brs,1H).

Example 1-202

MS ESI m/e: 499, 501 (M+H), 497, 499 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.82 (m, 2H), 0.98-1.06 (m, 2H),2.63-2.70 (m, 1H), 5.74 (s, 1H), 7.25-7.33 (m, 2H), 7.38-7.55 (m, 4H),7.63 (dd, J=2.2, 8.8 Hz, 1H), 7.92 (d, J=2.2 Hz, 1H), 10.90 (brs, 1H),11.14 (brs, 1H).

Example 1-203

MS ESI m/e: 482 (M+H).

¹H-NMR (DMSO-ds, 300 MHz) δ 0.77-0.79 (m, 2H), 1.02-1.17 (m, 2H), 2.18(s, 3H), 2.34 (s, 3H), 2.57 (s, 3H), 2.65-2.68 (m, 1H), 3.66 (s, 3H),5.24 (s, 1H), 6.98 (d, J=6.0 Hz, 1H), 7.29 (d, J=3.0 Hz, 1H), 7.40-7.56(m, 6H), 10.35 (brs, 1H).

Example 1-204

MS ESI m/e: 468 (M+H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.80 (m, 2H), 1.00-1.09 (m, 2H), 2.41(s, 3H), 2.57 (s, 3H), 2.62-2.71 (m, 1H), 3.68 (s, 3H), 5.26 (s, 1H),6.23 (s, 1H), 6.97 (d, J=12.0 Hz, 1H), 7.33 (s, 1H), 7.42-7.52 (m, 6H),10.35 (brs, 1H).

Example 1-205

MS ESI m/e: 547 (M+H), 545 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.86 (m, 2H), 1.18 (m, 2H), 2.75 (m, 1H), 2.89(s, 3H), 2.97 (s, 6H), 3.16 (t, J=4.8 Hz, 4H), 3.85 (t, J=4.8 Hz, 4H),5.45 (s, 1H), 6.45 (s, 1H), 6.49 (d, J=3.8 Hz, 1H), 6.75-6.80 (m, 2H),6.91 (d, J=8.3 Hz, 1H), 7.14 (t, J=9.0 Hz, 1H), 7.33 (t, J=8.4 Hz, 1H),9.89 (s, 1H).

Example 1-206

MS ESI m/e: 595, 597 (M+H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.77 (m, 2H), 0.98-1.07 (m, 2H), 2.21(s, 3H), 2.40-2.46 (m, 4H), 2.61-2.71 (m, 1H), 2.69 (s, 3H), 3.09-3.16(m, 4H), 5.37 (s, 1H), 6.79-6.84 (m, 1H), 6.96-7.03 (m, 2H), 7.29-7.34(m, 1H), 7.44-7.54 (m, 2H), 7.69-7.77 (m, 1H), 10.58 (brs, 1H).

Example 1-207

MS ESI m/e: 545 (M+H), 543 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.92 (m, 2H), 1.14-1.25 (m, 2H),2.72-2.82 (m, 1H), 2.82 (s, 3H), 5.69 (d, J=1.1 Hz, 1H), 7.28-7.36 (m,2H), 7.40-7.59 (m, 6H), 10.36 (s, 1H).

Example 1-208

MS ESI m/e: 443 (M+H), 441 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.81-0.91 (m, 2H), 1.16-1.23 (m, 2H),2.73-2.80 (m, 1H), 2.82 (s, 3H), 3.12 (s, 1H), 5.80 (s, 1H), 7.26-7.33(m, 3H), 7.35-7.52 (m, 5H), 10.50 (s, 1H).

Example 1-209

MS ESI m/e: 416 (M+H), 414 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.79-0.88 (m, 2H), 1.12-1.22 (m, 2H),2.68-2.77 (m, 1H), 2.79 (s, 3H), 4.42 (d, J=5.6 Hz, 2H), 5.37 (s, 1H),7.26-7.35 (m, 3H), 7.38-7.52 (m, 3H), 7.65-7.72 (m, 1H), 8.57 (dd,J=1.5, 4.9 Hz, 1H), 8.63 (d, J=1.9 Hz, 1H), 9.15 (t, J=5.3 Hz, 1H).

Example 1-210

MS ESI m/e: 511, 513 (M+H), 509, 511 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.80-0.90 (m, 2H), 1.13-1.23 (m, 2H),2.70-2.78 (m, 1H), 2.79 (s, 3H), 4.43 (d, J=6.0 Hz, 2H), 5.33 (s, 1H),6.98 (dd, J=9.0, 9.1 Hz, 1H), 7.28-7.33 (m, 2H), 7.35-7.53 (m, 5H), 9.12(t, J=6.0 Hz, 1H).

Example 1-211

MS ESI m/e: 509, 511 (M+H), 507, 509 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.83-0.92 (m, 2H), 1.14-1.25 (m, 2H),2.73-2.84 (m, 1H), 2.81 (s, 3H), 3.83 (s, 3H), 5.46 (s, 1H), 6.89 (dd,J=3.0, 8.7 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H), 7.29-7.36 (m, 3H), 7.38-7.54(m, 3H), 10.17 (brs, 1H).

Example 1-212

MS ESI m/e: 580, 581 (M+H), 578, 580 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.87 (m, 2H), 1.18 (m, 2H), 2.20 (m, 2H), 2.63(t, J=8.1 Hz, 2H), 2.77 (m, 1H), 2.88 (s, 3H), 3.88 (t, J=7.1 Hz, 2H),5.66 (s, 1H), 7.07 (d, J=7.9 Hz, 1H), 7.30-7.35 (m, 2H), 7.37 (d, J=9.2Hz, 1H), 7.46 (t, J=8.1 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.89 (d, J=2.0Hz, 1H), 10.34 (s, 1H).

Example 1-213

MS ESI m/e: 513, 515 (M+H), 511, 513 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 0.99-1.09 (m, 2H), 2.68(s, 3H), 2.61-2.71 (m, 1H), 5.35 (s, 1H), 2.79-2.89 (m, 3H), 7.27 (dd,J=9.0, 9.0 Hz, 1H), 7.48-7.52 (m, 2H), 7.72 (d, J=6.0 Hz, 1H), 9.83(brs, 1H), 10.53 (brs, 1H).

Example 1-214

MS ESI m/e: 594, 596 (M+H), 592, 594 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75 (m, 2H), 1.03 (m, 2H), 1.85 (brs, 4H),2.39 (m, 2H), 2.67 (m, 4H), 3.62 (m, 2H), 5.36 (s, 1H), 7.33 (d, J=8.3Hz, 1H), 7.35-7.40 (m, 2H), 7.45-7.55 (m, 3H), 7.74 (d, J=10.2 Hz, 1H),10.54 (s, 1H).

Example 1-215

MS ESI m/e: 566, 568 (M+H), 564, 566 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.80 (m, 2H), 0.99-1.11 (m, 2H),1.90-2.01 (m, 4H), 2.64-2.74 (m, 1H), 2.74-2.75 (m, 1H), 3.13-3.27 (m,4H), 5.39 (s, 1H), 6.54-6.65 (m, 3H), 7.20-7.30 (m, 1H), 7.45-7.55 (m,2H), 7.71-7.78 (m, 1H), 10.60 (brs, 1H).

Example 1-216

MS ESI m/e: 580, 582 (M+H), 578, 580 (M−H).

¹H-NMR (DMSO-d, 300 MHz) δ 0.69-0.78 (m, 2H), 0.98-1.08 (m, 2H),1.48-1.65 (m, 6H), 2.63-2.71 (m, 1H), 2.69 (s, 3H), 3.09-3.17 (m, 4H),5.37 (s, 1H), 6.72-6.79 (m, 1H), 6.95-7.02 (m, 2H), 7.25-7.32 (m, 1H),7.46-7.54 (m, 2H), 7.69-7.77 (m, 1H), 10.59 (brs, 1H).

Example 1-217

MS ESI m/e: 476 (M+H), 474 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.80 (m, 2H), 1.01-1.13 (m, 5H), 2.58(s, 3H), 2.61-2.72 (m, 1H), 2.90 (s, 3H), 3.42 (q, J=2.0 Hz, 2H), 5.04(s, 1H), 6.62 (dd, J=9.0, 15.0 Hz, 2H), 7.18 (t, J=9.0 Hz, 1H),7.40-7.59 (m, 5H), 10.01 (brs, 1H).

Example 1-218

MS ESI m/e: 584, 585 (M+H), 582, 584 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.78 (m, 2H), 0.98-1.09 (m, 2H), 2.18(s, 6H), 2.59 (t, J=3.0 Hz, 2H), 2.66 (s, 3H), 2.65-2.66 (m, 1H), 4.01(t, J=4.5 Hz, 2H), 5.37 (s, 1H), 6.96-7.08 (m, 3H), 7.38-7.51 (m, 3H),7.71 (d, J=12.0 Hz, 1H), 10.55 (brs, 1H).

Example 1-219

MS ESI m/e: 596, 598 (M+H), 594, 596 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75 (m, 2H), 1.03 (m, 2H), 2.67 (s, 4H),3.75 (m, 2H), 3.98 (t, J=4.9 Hz, 2H), 4.21 (s, 2H), 5.36 (s, 1H), 7.37(d, J=7.3 Hz, 1H), 7.40-7.60 (m, 5H), 7.73 (d, J=9.4 Hz, 1H), 10.53 (s,1H).

Example 1-220

MS ESI m/e: 571, 573 (M+H), 569, 571 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.76 (m, 2H), 0.99-1.10 (m, 2H),2.65-2.67 (m, 1H), 2.66 (s, 3H), 4.71 (s, 2H), 5.37 (s, 1H), 6.99-7.08(m, 3H), 7.41 (t, J=9.0 Hz, 1H), 7.45-7.52 (m, 2H), 7.74 (d, J=9.0 Hz,1H), 10.55 (brs, 1H), 13.04 (brs, 1H).

Example 1-221

MS ESI m/e: 527 (M+H), 525 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.91 (m, 2H), 1.14-1.25 (m, 2H),2.71-2.82 (m, 1H), 2.82 (s, 3H), 5.82 (s, 1H), 7.01-7.09 (m, 2H),7.28-7.35 (m, 2H), 7.39-7.54 (m, 3H), 7.66-7.74 (m, 2H), 10.42 (s, 1H).

Example 1-222

MS ESI m/e: 425 (M+H), 423 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.91 (m, 2H), 1.15-1.24 (m, 2H),2.71-2.83 (m, 1H), 2.83 (s, 3H), 3.09 (s, 1H), 5.92 (s, 1H), 7.22-7.29(m, 2H), 7.29-7.35 (m, 2H), 7.40-7.57 (m, 5H), 10.54 (s, 1H).

Example 1-223

MS ESI m/e: 575, 577 (M+H), 573, 575 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.84-0.91 (m, 2H), 1.17-1.26 (m, 2H),2.73-2.80 (m, 1H), 2.81 (s, 3H), 3.11 (s, 3H) 5.65 (s, 1H), 7.27-7.35(m, 2H), 7.35-7.40 (min, 1H), 7.51-7.56 (m, 1H), 7.68-7.75 (m, 1H),8.00-8.05 (m, 2H), 10.22 (s, 1H).

Example 1-224

MS ESI m/e: 604, 606 (M+H), 602, 604 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.91 (m, 2H), 1.15-1.27 (m, 2H),2.72-2.81 (m, 1H), 2.76 (s, 6H), 2.81 (s, 3H), 5.65 (d, J=1.1 Hz, 1H),7.29-7.34 (m, 2H), 7.35-7.43 (m, 1H), 7.45-7.51 (m, 1H), 7.63-7.72 (m,1H), 7.83-7.89 (m, 2H), 10.25 (s, 1H).

Example 1-225

MS ESI m/e: 575, 577 (M+H), 573, 575 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.91 (m, 2H), 1.16-1.27 (m, 2H),2.72-2.83 (m, 1H), 2.83 (brs, 3H), 3.10 (s, 3H), 5.63 (brs, 1H),7.28-7.35 (m, 2H), 7.36-7.42 (m, 1H), 7.58 (d, J=8.4 Hz, 2H), 8.10 (d,J=8.4 Hz, 2H), 10.22 (s, 1H).

Example 1-226

MS ESI m/e: 604, 606 (M+H), 602, 604 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.83-0.91 (m, 2H), 1.17-1.25 (m, 2H),2.71-2.81 (m, 1H), 2.75 (s, 6H), 2.84 (brs, 3H), 5.58 (brs, 1H),7.26-7.35 (m, 2H), 7.35-7.40 (m, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.89 (d,J=8.1 Hz, 2H), 10.21 (s, 1H).

Example 1-227

MS ESI m/e: 598, 600 (M+H), 596, 598 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.78 (m, 2H), 0.99-1.09 (m, 2H), 1.84(t, J=6.0 Hz, 2H), 2.13 (s, 6H), 2.34 (t, J=6.0 Hz, 2H), 2.66-2.68 (m,1H), 2.67 (s, 3H), 4.00 (t, J=6.0 Hz, 2H), 5.37 (s, 1H), 6.96-7.09 (m,3H), 7.40 (dd, J=6.0, 6.0 Hz, 1H), 7.48-7.51 (m, 2H), 7.74 (d, J=9.0 Hz,1H), 10.56 (brs, 1H).

Example 1-228

MS ESI m/e: 604, 606 (M+H), 602, 604 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.80 (m, 2H), 0.98-1.10 (m, 2H),2.61-2.71 (m, 1H), 2.68 (s, 3H), 2.96 (s, 3H), 3.25 (s, 3H), 5.37 (s,1H), 7.39 (d, J=6.0 Hz, 18H), 7.45-7.58 (m, 5H), 7.74 (d, J=9.0 Hz, 1H),10.53 (brs, 1H).

Example 1-229

MS ESI m/e: 443 (M+H), 441 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.90 (m, 2H), 1.14-1.24 (m, 2H), 1.27 (d,J=7.1 Hz, 6H), 2.72-2.81 (m, 1H), 2.81 (s, 3H), 2.92 (sept, J=6.8 Hz,1H), 5.77 (s, 1H), 7.16-7.22 (m, 28), 7.22-7.28 (m, 2H), 7.29-7.35 (m,2H), 7.39-7.53 (m, 3H), 10.28 (brs, 1H).

Example 1-230

MS ESI m/e: 429 (M+H), 427 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.91 (m, 2H), 1.15-1.24 (m, 2H), 1.25 (t,J=7.5 Hz, 3H), 2.66 (q, J=7.5 Hz, 2H), 2.72-2.81 (m, 1H), 2.81 (s, 3H),5.76 (s, 1H), 7.15-7.24 (m, 4H), 7.29-7.36 (m, 2H), 7.39-7.53 (m, 3H),10.29 (brs, 1H).

Example 1-231

MS ESI m/e: 426 (M+H), 424 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.90 (m, 2H), 1.15-1.25 (m, 2H),2.72-2.82 (m, 1H), 2.84 (s, 3H), 6.07 (s, 1H), 7.28-7.34 (m, 2H),7.36-7.42 (m, 2H), 7.44-7.55 (m, 3H), 7.64-7.70 (m, 2H), 10.84 (brs,1H).

Example 1-232

MS ESI m/e: 626, 628 (M+H), 624, 626 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 1.01-1.09 (min, 2H),2.41-2.48 (m, 4H), 2.67 (s, 3H), 2.64-2.70 (m, 3H), 3.45-3.60 (m, 4H),4.06-4.10 (m, 2H), 5.36 (s, 1H), 7.00 (d, J=3.0 Hz, 1H), 7.03-7.05 (m,2H), 7.38-0.53 (m, 3H), 7.72 (d, J=6.0 Hz, 1H), 10.54 (brs, 1H).

Example 1-233

MS ESI m/e: 610, 612 (M+H), 608, 610 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 1.00-1.09 (m, 2H),1.62-1.71 (m, 4H), 2.43-2.55 (m, 4H), 2.64 (s, 3H), 2.61-2.70 (m, 1H),2.77 (t, J=3.0 Hz, 2H), 4.06 (t, J=3.0 Hz, 2H), 5.37 (s, 1H), 6.99 (d,J=3.0 Hz, 1H), 7.02-7.04 (m, 2H), 7.39 (dd, J=3.0, 3.0 Hz, 1H),7.50-7.52 (m, 2H), 7.74 (d, J=3.0 Hz, 1H), 10.54 (brs, 1)

Example 1-234

MS ESI m/e: 624, 626 (M+H), 622, 624 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 1.01-1.09 (m, 2H),1.32-1.41 (m, 2H), 1.41-1.52 (m, 4H), 2.37-2.46 (m, 4H), 2.60-2.71 (m,3H), 2.67 (s, 3H), 4.07 (t, J=6.0 Hz, 2H), 5.38 (s, 1H), 7.01 (dd,J=6.0, 9.0 Hz, 1H), 7.05-7.06 (m, 2H), 7.40 (dd, J=9.0, 9.0 Hz, 1H),7.49-7.51 (m, 2H), 7.74 (d, J=12.0 Hz, 1H), 10.55 (brs, 1H).

Example 1-235

MS ESI m/e: 612, 614 (M+H), 610, 612 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 0.96 (t, J=7.5 Hz, 6H),0.99-1.09 (m, 2H), 2.46-2.59 (m, 5H), 2.68 (s, 3H), 2.75 (t, J=3.0 Hz,2H), 4.00 (t, J=3.0 Hz, 2H), 5.37 (s, 1H), 7.00 (dd, J=3.0, 3.0 Hz, 1H),7.01-7.06 (m, 2H), 7.40 (dd, J=6.0, 3.0 Hz, 1H), 7.49-7.52 (m, 2H), 7.74(d, J=18.0 Hz, 1H), 10.56 (brs, 1H).

Example 1-236

MS ESI m/e: 653, 655 (M+H), 651, 653 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 0.96 (t, J=7.5 Hz, 6H),0.99-1.09 (m, 2H), 1.80-1.91 (m, 2H), 2.13 (s, 3H), 2.46-2.59 (m, 10H),2.60-2.73 (m, 4H), 4.00 (t, J=3.0 Hz, 2H), 5.37 (s, 1H), 7.00 (dd,J=3.0, 3.0 Hz, 1H), 7.01-7.06 (m, 2H), 7.40 (dd, J=6.0, 3.0 Hz, 1H),7.49-7.52 (m, 2H), 7.74 (d, J=18.0 Hz, 1H), 10.56 (brs, 1H).

Example 1-237

MS ESI m/e: 444 (M+H), 442 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.92 (m, 2H), 1.16-1.26 (m, 2H),2.73-2.83 (m, 1H), 2.85 (s, 3H), 6.01 (s, 1H), 7.29-7.35 (m, 2H),7.43-7.56 (m, 5H), 7.60-7.70 (m, 1H), 10.93 (s, 1H).

Example 1-238

MS ESI m/e: 473 (M+H), 471 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.71-0.79 (m, 2H), 1.00-1.08 (m, 2H), 2.60(s, 3H), 2.63-2.71 (m, 1H), 4.31 (d, J=5.8 Hz, 2H), 5.38 (t, J=5.9 Hz,1H), 5.50 (s, 1H), 7.29-7.35 (m, 1H), 7.39-7.58 (m, 7H), 10.71 (s, 1H).

Example 1-239

MS ESI m/e: 501 (M+H), 499 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.82-0.90 (m, 2H), 1.15-1.24 (m, 2H), 1.63 (s,6H), 2.07 (s, 1H), 2.73-2.81 (m, 1H), 2.82 (s, 3H), 5.78 (s, 1H),7.16-7.25 (m, 2H), 7.28-7.33 (m, 2H), 7.34-7.52 (m, 4H), 10.46 (s, 1H).

Example 1-240

MS ESI m/e: 445 (M+H), 443 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.84-0.90 (m, 2H), 1.16-1.24 (m, 2H),2.73-2.82 (m, 1H), 2.82 (s, 3H), 5.31 (d, J=10.9 Hz, 1H), 5.74 (d,J=17.6 Hz, 1H), 5.72 (s, 1H), 6.66 (dd, J=10.9, 17.8 Hz, 1H), 7.14-7.25(m, 2H), 7.28-7.39 (m, 3H), 7.40-7.51 (m, 3H), 10.34 (s, 1H).

Example 1-241

MS ESI m/e: 487 (M+H), 485 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.91 (m, 2H), 1.15-1.24 (m, 2H),2.73-2.83 (m, 1H), 2.83 (s, 3H), 3.47 (s, 3H), 4.33 (s, 2H), 5.79 (s,1H), 7.22-7.35 (m, 4H), 7.35-7.56 (m, 4H), 10.49 (s, 1H).

Example 1-242

MS ESI m/e: 447 (M+H), 445 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.84-0.90 (m, 2H), 1.15-1.22 (m, 2H), 1.25 (t,J=7.6 Hz, 3H), 2.66 (q, J=7.6 Hz, 2H), 2.73-2.81 (m, 1H), 2.81 (s, 3H),5.59 (d, J=1.2 Hz, 1H), 6.96-7.04 (m, 2H), 7.23-7.34 (m, 3H), 7.39-7.51(m, 3H), 10.16 (s, 1H).

Example 1-243

MS ESI m/e: 555, 557 (M+H), 553, 555 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.92 (m, 2H), 1.14-1.25 (m, 2H), 1.43 (t,J=4.9 Hz, 1H), 1.88 (quint, J=7.3 Hz, 2H), 2.72-2.81 (m, 1H), 2.76 (t,J=7.7 Hz, 2H), 2.82 (s, 3H), 3.65 (q, J=5.7 Hz, 2H), 5.66 (s, 1H),7.10-7.19 (m, 2H), 7.26-7.33 (m, 3H), 7.35-7.45 (m, 2H), 10.34 (brs,1H).

Example 1-244

MS ESI m/e: 486, 488 (M+H), 484, 486 (M−H).

¹H-NM R (DMSO-d₆, 300 MHz) δ 1.19 (t, J=6.0 Hz, 3H), 2.50-2.53 (m, 1H),2.62 (s, 3H), 3.95 (q, J=7.0 Hz, 2H), 5.37 (s, 1H), 7.48-7.52 (m, 2H),7.60 (dd, J=3.0, 3.0 Hz, 1H), 7.74 (d, J=12.0 Hz, 1H), 7.97 (d, J=6.0Hz, 1H), 8.73 (d, J=45.0 Hz, 1H), 10.58 (brs, 1H).

Example 1-245

MS ESI m/e: 554, 556 (M+H), 552, 554 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.79 (m, 2H), 0.99-1.09 (m, 2H), 2.04(s, 3H), 2.63-2.68 (m, 1H), 2.66 (s, 3H), 5.35 (s, 1H), 7.08 (d, J=9.0Hz, 1H), 7.41 (dd, J=6.0, 6.0 Hz, 1H), 7.49-7.51 (m, 2H), 7.61-7.77 (m,3H), 10.18 (brs, 1H), 10.54 (brs, 1H).

Example 1-246

MS ESI m/e: 500 (M+H), 498 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.91 (m, 2H), 1.14-1.25 (m, 2H), 2.38 (s,6H), 2.72-2.83 (m, 1H), 2.83 (s, 3H), 3.48 (s, 2H), 5.77 (d, J=0.7 Hz,1H), 7.20-7.55 (m, 8H), 10.45 (s, 1H).

Example 1-247

MS ESI m/e: 489 (M+H), 487 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.81 (m, 2H), 0.99-1.10 (m, 2H), 2.61(s, 3H), 2.64-2.74 (m, 1H), 5.57 (s, 1H), 6.58 (d, J=16.1 Hz, 1H),7.40-7.64 (m, 8H), 7.81 (d, J=12.1 Hz, 1H), 10.80 (s, 1H), 12.44 (brs,1H).

Example 1-248

MS ESI m/e: 491 (M+H), 489 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.72-0.78 (m, 2H), 0.99-1.07 (m, 2H), 2.59(t, J=7.6 Hz, 2H), 2.58 (s, 3H), 2.63-2.70 (m, 1H), 2.86 (t, J=7.5 Hz,2H), 5.25 (d, J=1.2 Hz, 1H), 7.12-7.17 (m, 1H), 7.24-7.30 (m, 1H),7.35-7.54 (m, 6H), 10.40 (s, 1H), 12.18 (s, 1H).

Example 1-249

MS ESI m/e: 447 (M+H), 445 (M−H).

¹H-NMR (DMSO-ds, 300 MHz) δ 0.72-0.79 (m, 2H), 0.99-1.07 (m, 2H), 2.59(s, 3H), 2.63-2.70 (m, 1H), 5.45 (s, 1H), 7.25-7.30 (m, 2H), 7.31-7.37(m, 2H), 7.41-7.55 (m, 5H), 10.49 (brs, 1H).

Example 1-250

MS ESI m/e: 501 (M+H), 499 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.78 (m, 2H), 1.00-1.08 (m, 2H), 2.62(s, 1H), 2.66-2.71 (m, 1H), 5.76 (s, 1H), 7.41-7.55 (m, 7H), 7.76 (d,J=8.3 Hz, 2H), 10.86 (brs, 1H).

Example 1-251

MS ESI m/e: 458 (M+H), 456 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.72-0.82 (m, 2H), 0.99-1.09 (m, 2H), 2.58 (s,3H), 2.63-2.74 (m, 1H), 5.13 (d, J=1.1 Hz, 1H), 6.45-6.50 (m, 1H),7.33-7.61 (m, 8H), 10.28 (brs, 1H), 11.28 (brs, 1H).

Example 1-252

MS ESI m/e: 582, 584 (M+H), 580, 582 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.91 (m, 2H), 1.14-1.25 (m, 2H),1.76-1.90 (m, 2H), 2.26-2.38 (m, 2H), 2.26 (brs, 6H), 2.65-2.73 (m, 2H),2.74-2.80 (m, 1H), 2.83 (s, 3H), 5.65 (d, J=0.7 Hz, 1H), 7.10-7.16 (m,2H), 7.24-7.29 (m, 1H), 7.30-7.34 (m, 2H), 7.34-7.44 (m, 2H), 10.34(brs, 1H).

Example 1-253

MS ESI m/e: 584, 586 (M+H), 582, 584 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.90 (m, 2H), 1.15-1.23 (m, 2H),2.73-2.80 (m, 1H), 2.93 (s, 3H), 2.97 (s, 3H), 3.34 (s, 3H), 3.44-3.56(m, 4H), 5.66 (d, J=1.1 Hz, 2H), 6.55-6.60 (m, 2H), 6.70-6.76 (m, 1H),7.22-7.40 (m, 4H), 10.39 (brs, 1H).

Example 1-254

MS ESI m/e: 457 (M+H), 455 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.82-0.89 (m, 2H), 1.15-1.23 (m, 2H), 2.06 (s,3H), 2.72-2.80 (m, 1H), 2.82 (s, 3H), 5.74 (s, 1H), 7.14-7.21 (m, 2H),7.28-7.36 (m, 3H), 7.39-7.51 (m, 3H), 10.38 (s, 1H).

Example 1-255

MS ESI m/e: 624, 626 (M+H), 622, 624 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.91 (m, 2H), 1.13-1.24 (m, 2H),1.74-1.90 (m, 2H), 2.28-2.38 (m, 2H), 2.38-2.46 (m, 4H), 2.65-2.72 (m,2H), 2.73-2.80 (m, 1H), 2.83 (s, 3H), 3.68-3.74 (m, 4H), 5.65 (d, J=1.1Hz, 1H), 7.10-7.17 (m, 2H), 7.23-7.28 (m, 1H), 7.29-7.33 (m, 2H),7.34-7.44 (m, 2H), 10.33 (brs, 1H).

Example 1-256

MS ESI m/e: 549 (M+H), 547 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.66-0.77 (m, 2H), 0.89-1.05 (m, 2H),2.54-2.61 (m, 1H), 2.56 (s, 3H), 7.36-7.45 (m, 4H), 7.53-7.63 (m, 3H),7.65-7.71 (m, 2H), 12.88 (brs, 1H).

Example 1-257

MS ESI m/e: 638 (M+H), 636 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74 (m, 2H), 1.03 (m, 2H), 2.65 (s, 4H),3.02 (s, 3H), 5.38 (s, 1H), 7.13 (d, J=8.6 Hz, 1H), 7.20-7.40 (m, 3H),7.46 (t, J=8.1 Hz, 1H), 7.63 (d, J=9.3 Hz, 1H), 7.81 (d, J=10.1 Hz, 1H),10.00 (s, 1H), 10.54 (s, 1H).

Example 1-258

MS ESI m/e: 461 (M+H), 459 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.83-0.91 (m, 2H), 0.96 (t, J=7.3 Hz, 3H),1.14-1.25 (m, 2H), 1.58-1.72 (m, 2H), 2.60 (t, J=7.7 Hz, 2H), 2.72-2.82(m, 1H), 2.82 (s, 3H), 5.61 (d, J=1.1 Hz, 1H), 6.94-7.04 (m, 2H),7.24-7.36 (m, 3H), 7.41-7.53 (m, 3H), 10.18 (s, 1H).

Example 1-259

MS ESI m/e: 521 (M+H), 519 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.83-0.92 (m, 2H), 1.17-1.27 (m, 2H),2.72-2.82 (m, 1H), 2.82 (s, 3H), 3.12 (s, 3H), 3.14 (s, 1H), 5.80 (d,J=0.7 Hz, 18H), 7.28-7.36 (m, 2H), 7.37-7.45 (m, 1H), 7.51-7.57 (m, 1H),7.68-7.77 (m, 1H), 8.01-8.07 (m, 2H), 10.40 (s, 1H).

Example 1-260

MS ESI m/e: 536 (M+H), 534 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.82-0.93 (m, 2H), 1.29-1.28 (m, 2H),2.71-2.81 (m, 1H), 2.89 (s, 3H), 3.10 (s, 3H), 3.15 (s, 1H), 5.82 (s,1H), 6.81-6.88 (m, 1H), 7.08 (d, J=9.0 Hz, 1H), 7.21-7.39 (m, 3H),7.39-7.51 (m, 2H), 10.49 (brs, 1H).

Example 1-261

MS ESI m/e: 499, 501 (M+H).

¹H-NMR (CDCl₃, 300 MHz) δ 1.30 (t, J=7.0 Hz, 3H), 3.63 (s, 3H), 4.13 (q,J=7.0 Hz, 2H), 5.57 (s, 2H), 5.78 (s, 1H), 7.20-7.50 (m, 8H), 10.33 (s,1H).

Example 1-262

MS ESI m/e: 604, 606 (M+H), 602, 604 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.78 (m, 2H), 0.99-1.07 (m, 2H), 1.18(t, J=7.5 Hz, 3H), 2.61-2.70 (m, 4H), 3.13 (q, J=7.0 Hz, 2H), 5.35 (s,1H), 7.08-7.14 (m, 1H), 7.25-7.34 (m, 2H), 7.41-7.54 (m, 3H), 7.71-7.77(m, 1H), 10.04 (brs, 1H), 10.53 (s, 1H).

Example 1-263

MS ESI m/e: 570, 572 (M+H), 568, 570 (M−H).

¹H-NMR (DMSO-ds, 300 MHz) δ 0.71-0.79 (m, 2H), 0.99-1.07 (m, 2H),2.63-2.73 (m, 1H), 2.66 (s, 3H), 3.99 (d, J=6.0 Hz, 2H), 5.36 (s, 1H),5.65 (t, J=6.0 Hz, 1H), 7.10-7.15 (m, 18H), 7.39-7.52 (m, 3H), 7.71-7.85(m, 3H), 9.91 (brs, 1H), 10.54 (brs, 1H).

Example 1-264

MS ESI m/e: 512, 514 (M+H), 510, 512 (M−H).

¹H-NMR (DMSO-ds, 300 MHz) δ 0.69-0.77 (m, 2H), 0.97-1.08 (m, 2H),2.62-2.71 (m, 1H), 2.74 (s, 3H), 5.35 (d, J=1.5 Hz, 1H), 5.38 (brs, 2H),6.47-6.53 (m, 1H), 6.54-6.57 (m, 1H), 6.58-6.63 (m, 1H), 7.11 (t, J=7.9Hz, 1H), 7.44-7.53 (m, 2H), 7.70-7.77 (m, 1H), 10.55 (brs, 1H).

Example 1-265

MS ESI m/e: 459 (M+H), 457 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.66-0.74 (m, 2H), 0.83-0.91 (m, 2H),0.97-1.06 (m, 2H), 1.14-1.24 (m, 2H), 1.85-1.96 (m, 1H), 2.72-2.81 (m,1H), 2.81 (s, 3H), 5.58 (d, J=1.1 Hz, 1H), 6.82-6.92 (m, 2H), 7.21-7.29(m, 1H), 7.29-7.36 (m, 2H), 7.39-7.53 (m, 3H), 10.16 (s, 1H).

Example 1-266

MS ESI m/e: 584, 586 (M+H), 582, 584 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.78 (m, 2H), 0.99-1.08 (m, 2H),2.63-2.71 (m, 1H), 2.66 (s, 3H), 3.32 (s, 3H), 3.37 (s, 3H), 4.00 (brs,2H), 5.36 (d, J=0.8 Hz, 1H), 7.10-7.16 (m, 1H), 7.40-7.52 (m, 3H),7.71-7.80 (m, 3H), 10.00 (brs, 1H), 10.54 (brs, 1H).

Example 1-267

MS ESI m/e: 658, 660 (M+H), 656, 658 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.70-0.79 (m, 2H), 0.99-1.10 (m, 2H),2.62-2.76 (m, 1H), 2.66 (s, 3H), 4.48-4.64 (m, 2H), 5.36 (s, 1H), 7.17(d, J=9.0 Hz, 1H), 7.28-7.33 (m, 2H), 7.43-7.52 (m, 3H), 7.74 (d, J=12.0Hz, 1H), 10.52 (brs, 1H), 10.72 (brs, 1H).

Example 1-268

MS ESI m/e: 554 (M+H), 552 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.83-0.92 (m, 2H), 1.14-1.24 (m, 2H), 1.26 (t,J=7.7 Hz, 3H), 1.37 (t, J=7.3 Hz, 3H), 2.67 (q, J=7.6 Hz, 2H), 2.71-2.81(m, 1H), 2.85 (s, 3H), 3.17 (q, J=7.5 Hz, 2H), 5.60 (d, J=1.1 Hz, 1H),6.94-7.08 (m, 4H), 7.22-7.33 (m, 3H), 7.38-7.47 (m, 1H), 10.15 (s, 1H).

Example 1-269

MS EST m/e: 541, 543 (M+H), 539, 541 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.79 (m, 2H), 0.98-1.10 (m, 2H), 2.60(s, 3H), 2.62-2.71 (m, 1H), 5.37 (d, J=1.1 Hz, 1H), 7.43-7.57 (m, 2H),7.61-7.78 (m, 3H), 7.95-8.05 (m, 2H), 10.54 (brs, 1H), 13.34 (brs, 1H).

Example 1-270

MS ESI m/e: 540, 542 (M+H), 538, 540 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.80 (m, 2H), 0.98-1.09 (m, 2H), 2.61(s, 3H), 2.63-2.74 (m, 1H), 5.38 (s, 1H), 7.45-7.58 (m, 3H), 7.58-7.65(m, 2H), 7.70-7.78 (m, 1H), 7.90 (brs, 1H), 7.94-8.00 (m, 1H), 8.11(brs, 1H), 10.54 (brs, 1H).

Example 1-271

MS ESI m/e: 618, 620 (M+H), 616, 618 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.77 (m, 2H), 0.92 (t, J=7.5 Hz, 3H),1.00-1.07 (m, 2H), 1.66 (q, J=7.0 Hz, 2H), 2.62-2.70 (m, 4H), 3.05-3.13(m, 2H), 5.36 (s, 1H), 7.09-7.13 (m, 1H), 7.23-7.32 (m, 2H), 7.41-7.53(m, 3H), 7.71-7.77 (m, 1H), 10.05 (brs, 1H), 10.53 (s, 1H).

Example 1-272

MS ESI m/e: 618, 620 (M+H), 616, 618 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.78 (m, 2H), 0.99-1.08 (m, 2H), 1.23(d, J=6.0 Hz, 6H), 2.62-2.70 (m, 4H), 3.19-3.29 (m, 1H), 5.36 (s, 1H),7.07-7.13 (m, 1H), 7.26-7.34 (m, 2H), 7.39-7.54 (m, 3H), 7.71-7.76 (m,1H), 10.00 (brs, 1H), 10.53 (s, 1H).

Example 1-273

MS ESI m/e: 469 (M+H), 467 (M−1).

¹H-NMR (CDCl₃, 300 MHz) δ 0.80-0.90 (m, 2H), 1.10-1.30 (m, 2H), 2.78 (m,1H), 2.83 (s, 3H), 5.97 (s, 1H), 7.30-7.35 (m, 2H), 7.35-7.55 (m, 5H),7.65 (d, J=8.5 Hz, 2H), 10.67 (s, 1H).

Example 1-274

MS ESI m/e: 652 (M+H), 650 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.79 (m, 2H), 0.98-1.08 (m, 2H), 1.17(t, J=7.3 Hz, 3H), 2.61-2.71 (m, 1H), 2.64 (s, 3H), 3.13 (q, J=7.3 Hz,2H), 5.38 (brs, 1H), 7.09-7.15 (m, 2H), 7.24-7.38 (m, 3H), 7.40-7.49 (m,1H), 7.60-7.67 (m, 1H), 7.81 (dd, J=1.8, 9.9 Hz, 1H), 10.04 (s, 1H).

Example 1-275

MS ESI m/e: 540 (M+H), 538 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.83-0.91 (m, 2H), 1.15-1.23 (m, 2H), 1.26 (t,J=7.6 Hz, 3H), 2.67 (q, J=7.6 Hz, 2H), 2.72-2.80 (m, 1H), 2.85 (s, 3H),3.05 (s, 3H), 5.60 (d, J=1.2 Hz, 1H), 6.98-7.05 (m, 2H), 7.05-7.10 (m,1H), 7.23-7.31 (m, 4H), 7.40-7.47 (m, 1H), 10.16 (s, 1H).

Example 1-276

MS ESI m/e: 653, 655 (M+H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.79 (m, 2H), 0.87 (t, J=7.2 Hz, 3H),1.00-1.08 (m, 2H), 1.22-1.36 (m, 2H), 1.43-1.54 (m, 2H), 2.15 (t, J=7.3Hz, 2H), 2.63-2.72 (m, 1H), 2.66 (s, 3H), 3.86 (d, J=5.3 Hz, 2H), 5.36(s, 1H), 7.05-7.12 (m, 1H), 7.40-7.52 (m, 3H), 7.61-7.77 (m, 3H),8.08-8.15 (m, 1H), 10.20 (brs, 1H), 10.54 (brs, 1H).

Example 1-277

MS ESI m/e: 597, 599 (M+H), 595, 597 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.78 (m, 2H), 0.99-1.07 (m, 2H), 2.28(s, 6H), 2.64-2.70 (m, 1H), 2.67 (s, 3H), 3.09 (brs, 2H), 5.36 (d, J=1.1Hz, 1H), 7.10-7.14 (m, 1H), 7.40-7.52 (m, 3H), 7.71-7.79 cm, 3H), 9.97(brs, 1H), 10.54 (brs, 1H).

Example 1-278

MS ESI m/e: 568, 570 (M+H), 566, 568 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.78 (m, 2H), 0.99-1.11 (m, 5H), 2.33(q, J=7.0 Hz, 2H), 2.63-2.71 (m, 4H), 5.36 (s, 1H), 7.04-7.10 (m, 1H),7.42 (t, J=7.5 Hz, 1H), 7.46-7.54 (m, 2H), 7.61-7.67 (m, 1H), 7.70-7.77(m, 2H), 10.08 (s, 1H), 10.54 (s, 1H).

Example 1-279

MS ESI m/e: 582, 584 (M+H), 580, 582 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.78 (m, 2H), 0.91 (t, J=7.5 Hz, 3H),0.99-1.07 (m, 2H), 1.60 (q, J=8.0 Hz, 2H), 2.29 (t, J=7.5 Hz, 2H),2.63-2.71 (m, 4H), 5.36 (s, 18H), 7.42 (t, J=7.5 Hz, 1H), 7.46-7.54 (m,2H), 7.62-7.76 (m, 3H), 10.09 (s, 1H), 10.54 (s, 1H).

Example 1-280

MS ESI m/e: 644, 646 (M+H), 642, 644 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.68-0.80 (m, 2H), 0.97-1.08 (m, 2H),2.61-2.72 (m, 1H), 2.64 (s, 3H), 5.36 (d, J=0.7 Hz, 1H), 6.88-7.01 (m,1H), 7.05-7.17 (m, 2H), 7.23-7.34 (m, 1H), 7.47 (dd, J=2.3, 8.7 Hz, 1H),7.52 (t, J=8.1 Hz, 1H), 7.73 (dd, J=1.5, 10.2 Hz, 18H), 10.56 (brs, 1H).

Example 1-281

MS ESI m/e: 485 (M+H), 483 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.71-0.81 (m, 2H), 1.00-1.10 (m, 2H), 2.60 (s,3H), 2.61-2.72 (m, 1H), 5.52 (s, 1H), 7.41-7.56 (m, 9H), 10.62 (brs,1H).

Example 1-282

MS ESI m/e: 624, 626 (M+H), 622, 624 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.71-0.81 (m, 2H), 0.97-1.10 (m, 2H),2.61-2.72 (m, 1H), 2.65 (s, 3H), 5.07 (s, 2H), 5.36 (s, 1H), 7.19 (d,J=9.0 Hz, 1H), 7.28-7.38 (m, 2H), 7.42-7.56 (m, 38), 7.74 (d, J=9.0 Hz,1H), 10.53 (brs, 1H), 10.64 (brs, 1H).

Example 1-283

MS ESI m/e: 526, 528 (M+H), 524, 526 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.71-0.79 (m, 2H), 0.99-1.09 (m, 2H), 2.66 (d,J=6.0 Hz, 3H), 2.64-2.67 (m, 1H), 2.74 (s, 3H), 5.36 (s, 1H), 5.92-5.98(m, 1H), 6.50-6.60 (m, 3H), 7.19 (t, J=7.5 Hz, 1H), 7.49-7.54 (m, 2H),7.74 (d, J=12.0 Hz, 1H), 10.57 (brs, 1H).

Example 1-284

MS ESI m/e: 652, 654 (M+H), 650, 652 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.68-0.80 (m, 2H), 0.99-1.09 (m, 2H), 2.33 (s,3H), 2.61-2.70 (m, 1H), 5.35 (s, 1H), 7.04 (d, J=12.0 Hz, 1H), 7.13 (d,J=6.0 Hz, 1H), 7.30-7.38 (m, 2H), 7.49-7.62 (m, 5H), 7.73-7.80 (m, 3H),10.48 (brs, 1H), 10.52 (brs, 1H).

Example 1-285

MS ESI m/e: 465 (M+H), 463 (M−H).

¹H-NMR (DMSO-ds, 300 MHz) δ 0.71-0.78 (m, 2H), 1.01-1.07 (m, 2H), 2.53(s, 3H), 2.59 (s, 3H), 2.64-2.72 (m, 1H), 5.25 (d, J=1.1 Hz, 1H), 7.17(dd, J=1.9, 8.7 Hz, 1H), 7.32 (dd, J=1.9, 11.3 Hz, 1H), 7.39-7.55 (m,6H), 10.41 (brs, 1H).

Example 1-286

MS ESI m/e: 558 (M+H), 556 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.78 (m, 2H), 0.99-1.07 (m, 2H), 2.53(s, 3H), 2.63-2.69 (m, 1H), 2.65 (s, 3H), 3.02 (s, 3H), 5.25 (d, J=1.1Hz, 1H), 7.11-7.19 (m, 2H), 7.24-7.35 (m, 3H), 7.39-7.50 (m, 2H), 9.99(brs, 1H), 10.39 (brs, 1H).

Example 1-287

MS ESI m/e: 582, 584 (M+H), 580, 582 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.78 (m, 2H), 0.99-1.12 (m, 8H),2.53-2.70 (m, 5H), 5.36 (s, 1H), 7.05-7.11 (m, 1H), 7.42 (t, J=7.5 Hz,1H), 7.46-7.55 (m, 2H), 7.62-7.68 (m, 1H), 7.70-7.77 (m, 2H), 10.05 (s,1H), 10.54 (s, 1H).

Example 1-288

MS ESI m/e: 576, 578 (M+H), 574, 576 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.80 (m, 2H), 1.00-1.08 (m, 2H),2.60-2.70 (m, 4H), 5.37 (s, 1H), 7.47-7.58 (m, 4H), 7.65-7.77 (m, 3H),7.88-7.93 (m, 2H), 10.52 (s, 1H).

Example 1-289

MS ESI m/e: 550 (M+H), 548 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.78 (m, 2H), 0.99-1.09 (m, 2H), 1.18(t, J=7.3 Hz, 3H), 2.63-2.71 (m, 1H), 2.66 (s, 3H), 3.13 (q, J=7.5 Hz,2H), 4.32 (s, 1H), 5.51 (s, 1H), 7.09-7.15 (m, 1H), 7.24-7.35 (m, 2H),7.36-7.41 (m, 1H), 7.41-7.49 (m, 1H), 7.50-7.61 (m, 2H), 10.04 (s, 1H),10.72 (s, 1H).

Example 1-290

MS ESI m/e: 518 (M+H), 516 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.71-0.78 (m, 2H), 1.00-1.08 (m, 2H),2.61-2.71 (m, 1H), 2.66 (s, 3H), 3.03 (s, 3H), 4.19 (s, 1H), 5.64 (s,1H), 7.11-7.16 (m, 1H), 7.24-7.29 (m, 1H), 7.30-7.37 (m, 3H), 7.43-7.49(m, 1H), 7.51-7.56 (m, 2H), 10.01 (s, 1H), 10.70 (s, 1H).

Example 1-291

MS ESI m/e: 483 (M+H), 481 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.80 (m, 2H), 0.98-1.10 (m, 2H), 2.60(s, 3H), 2.62-2.73 (m, 1H), 3.68 (q, J=11.6 Hz, 2H), 5.54 (s, 1H),7.30-7.38 (m, 2H), 7.39-7.56 (m, 7H), 10.60 (brs, 1H).

Example 1-292

MS ESI m/e: 554, 556 (M+H), 552, 554 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.81 (m, 2H), 0.98-1.09 (m, 2H), 2.60(s, 3H), 2.63-2.71 (m, 1H), 2.79 (d, J=4.5 Hz, 3H), 5.38 (d, J=1.1 Hz,1H), 7.45-7.55 (m, 2H), 7.57-7.65 (m, 2H), 7.71-7.77 (m, 1H), 7.84-7.89(m, 1H), 7.89-7.95 (m, 1H), 8.57 (q, J=5.3 Hz, 1H), 10.53 (brs, 1H).

Example 1-293

MS ESI m/e: 447 (M+H), 445 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.80 (m, 2H), 0.99-1.08 (m, 2H), 2.59(s, 3H), 2.62-2.73 (m, 1H), 3.00 (dt, J=25.2, 6.0 Hz, 2H), 4.67 (dt,J=47.1, 6.4 Hz, 2H), 5.46 (s, 1H), 7.23-7.29 (m, 2H), 7.33-7.39 (m, 2H),7.40-7.56 (m, 5H), 10.51 (brs, 1H).

Example 1-294

MS ESI m/e: 590, 592 (M+H), 588, 590 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 1.00-1.09 (m, 2H), 2.42(s, 3H), 2.58-2.70 (m, 4H), 5.37 (s, 1H), 7.45-7.54 (m, 2H), 7.70-7.80(m, 3H), 7.82-7.88 (m, 2H), 10.51 (s, 1H).

Example 1-295

MS ESI m/e: 604, 606 (M+H), 602, 604 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.79 (m, 2H), 0.96 (t, J=6.0 Hz, 3H),1.01-1.08 (m, 2H), 2.58-2.71 (m, 4H), 2.74-2.84 (m, 2H), 5.37 (s, 1H),7.46-7.55 (m, 2H), 7.69-7.79 (m, 4H), 7.84-7.90 (m, 2H), 10.51 (s, 1H).

Example 1-296

MS ESI m/e: 504 (M+H), 502 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.91 (m, 2H), 1.12-1.23 (m, 2H), 1.26 (t,J=7.5 Hz, 3H), 2.16 (s, 3H), 2.66 (q, J=7.6 Hz, 2H), 2.72-2.82 (m, 1H),2.86 (s, 3H), 5.59 (d, J=1.5 Hz, 1H), 6.95-7.08 (m, 3H), 7.22-7.32 (m,1H), 7.33-7.55 (m, 3H), 7.70 (s, 1H), 10.18 (s, 1H).

Example 1-297

MS ESI m/e: 602 (M+H), 600 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.68-0.79 (m, 2H), 0.98-1.09 (m, 2H), 2.04(s, 3H), 2.63-2.71 (m, 1H), 2.66 (s, 3H), 5.38 (d, J=1.5 Hz, 1H),7.04-7.10 (m, 1H), 7.29-7.38 (m, 1H), 7.38-7.46 (m, 1H), 7.60-7.72 (m,3H), 7.81 (dd, J=1.8, 10.2 Hz, 1H), 10.15 (s, 1H), 10.55 (s, 1H).

Example 1-298

MS EST m/e: 532 (M+H), 530 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.80 (m, 2H), 0.98-1.09 (m, 2H), 1.18(t, J=7.3 Hz, 3H), 2.61-2.72 (m, 1H), 2.65 (s, 3H), 3.13 (q, J=7.5 Hz,2H), 4.18 (s, 1H), 5.65 (s, 1H), 7.08-7.15 (m, 1H), 7.24-7.31 (m, 1H),7.31-7.38 (m, 3H), 7.41-7.49 (m, 1H), 7.51-7.57 (m, 2H), 10.04 (s, 1H),10.70 (s, 1H).

Example 1-299

MS ESI m/e: 667, 669 (M+H), 665, 667 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.77 (m, 2H), 0.83 (t, J=7.4 Hz, 3H),0.98-1.07 (m, 2H), 1.19-1.29 (m, 2H), 1.39-1.49 (m, 2H), 2.04 (t, J=7.5Hz, 2H), 2.45-2.53 (m, 2H), 2.63-2.70 (m, 1H), 2.66 (s, 3H), 3.27-3.35(m, 2H), 5.35 (d, J=1.1 Hz, 1H), 7.05-7.11 (m, 1H), 7.42 (t, J=8.1 Hz,1H), 7.47-7.52 (m, 2H), 7.60-7.67 (m, 1H), 7.70-7.77 (m, 2H), 7.87-7.94(m, 1H), 10.17 (brs, 1H), 10.54 (brs, 1H).

Example 1-30.0

MS ESI m/e: 457 (M+H), 455 (M−1).

¹H-NMR (CDCl₃, 300 MHz) δ 0.80-0.90 (m, 2H), 1.10-1.30 (m, 2H), 1.34 (s,9H), 2.77 (m, 1H), 2.81 (s, 3H), 5.79 (s, 1H), 7.20 (d, J=8.5 Hz, 2H),7.30-7.35 (m, 2H), 7.35-7.55 (m, 5H), 10.29 (S, 1H).

Example 1-301

MS ESI m/e: 580 (M+H), 578 (M−1).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75 (brs, 2H), 1.05 (m, 2H), 2.68 (s, 4H),3.03 (s, 3H), 3.32 (s, 3H), 5.68 (s, 1H), 7.1.5 (d, J=8.9 Hz, 1H), 7.27(d, J=8.1 Hz, 1), 7.47 (t, J=8.0 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H),7.75-7.90 (m, 2H), 10.01 (s, 1H), 10.95 (s, 1H).

Example 1-302

MS ESI m/e: 620 (M+H), 618 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.71-0.78 (m, 2H), 0.99-1.07 (m, 2H),2.62-2.69 (m, 1H), 2.65 (s, 3H), 3.02 (s, 3H), 5.54 (s, 1H), 7.10-7.19(m, 3H), 7.23-7.28 (m, 1H), 7.29-7.32 (m, 1H), 7.42-7.49 (m, 1H),7.74-7.80 (m, 2H), 10.00 (s, 1H), 10.57 (s, 1H).

Example 1-303

MS ESI m/e: 625, 627 (M+H), 623, 625 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.78 (m, 2H), 0.99-1.09 (m, 2H),2.34-2.56 (m, 6H), 2.61-2.71 (m, 1H), 2.74 (s, 3H), 3.08-3.19 (m, 2H),3.50-3.62 (m, 4H), 5.36 (s, 1H), 5.77 (brs, 1H), 6.53-6.70 (m, 3H), 7.18(dd, J=9.0, 6.0 Hz, 1H), 7.40-7.50 (m, 2H), 7.74 (d, J=9.0 Hz, 1H),10.56 (brs, 1H).

Example 1-304

MS ESI m/e: 572, 574 (M+H), 570, 572 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.79 (m, 2H), 1.00-1.08 (m, 2H),2.62-2.68 (m, 4H), 3.02 (s, 3H), 5.53 (s, 1H), 7.12-7.14 (m, 1H),7.22-7.35 (m, 4H), 7.42-7.44 (m, 1H), 7.60-7.62 (m, 2H), 10.00 (brs,1H), 10.57 (brs, 1H).

Example 1-305

MS ESI m/e: 584, 586 (M+H), 582, 584 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.80 (m, 2H), 0.97-1.08 (m, 2H), 2.47(t, J=7.2 Hz, 2H), 2.62-2.71 (m, 1H), 2.67 (s, 3H), 3.70 (q, J=5.9 Hz,2H), 4.69 (t, J=5.1 Hz, 1H), 5.36 (d, J=1.1 Hz, 1H), 7.07 (dd, J=2.6,7.9 Hz, 1H), 7.42 (t, J=8.1 Hz, 1H), 7.48-7.55 (m, 2H), 7.62-7.69 (m,1H), 7.71-7.77 (m, 2H), 10.13 (brs, 1H), 10.54 (brs, 1H).

Example 1-306

MS ESI m/e: 611, 613 (M+H), 609, 611 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.79 (m, 2H), 0.98-1.08 (m, 2H), 2.16(s, 6H), 2.39-2.48 (m, 2H), 2.51-2.59 (m, 2H), 2.63-2.72 (m, 1H), 2.67(s, 3H), 5.35 (d, J=1.1 Hz, 1H), 7.05-7.11 (m, 1H), 7.42 (t, J=8.1 Hz,1H), 7.47-7.55 (m, 2H), 7.61-7.67 (m, 1H), 7.69-7.77 (m, 2H), 10.22(brs, 1H), 10.54 (brs, 1H).

Example 1-307

MS ESI m/e: 583, 585 (M+H), 581, 583 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.79 (m, 2H), 0.98-1.08 (m, 2H), 1.04(t, J=7.2 Hz, 3H), 2.62-2.74 (m, 1H), 2.68 (s, 3H), 3.09 (quint, J=6.8Hz, 2H), 5.35 (d, J=1.1 Hz, 1H), 6.16 (t, J=5.8 Hz, 1H), 6.88-6.95 (m,1H), 7.32 (t, J=7.9 Hz, 1H), 7.36-7.42 (m, 1H), 7.45-7.57 (m, 3H),7.71-7.77 (m, 1H), 8.73 (brs, 1H), 10.55 (brs, 1H).

Example 1-308

MS ESI m/e: 584, 586 (M+H), 582, 584 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.78 (m, 2H), 0.98-1.08 (m, 2H), 1.24(t, J=7.2 Hz, 3H), 2.61-2.72 (m, 1H), 2.66 (s, 3H), 4.12 (q, J=6.9 Hz,2H), 5.36 (d, J=1.1 Hz, 1H), 7.00-7.05 (m, 1H), 7.39 (t, J=7.9 Hz, 1H),7.43-7.55 (m, 3H), 7.60-7.65 (m, 1H), 7.70-7.78 (m, 1H), 9.85 (brs, 1H),10.54 (brs, 1H).

Example 1-309

MS ESI m/e: 619, 621 (M+H), 617, 619 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.68-0.80 (m, 2H), 0.98-1.07 (m, 2H),2.60-2.71 (m, 1H), 2.63 (s, 3H), 2.67 (s, 6H), 5.35 (d, J=1.1 Hz, 1H),7.09-7.15 (m, 1H), 7.21-7.27 (m, 2H), 7.43 (t, J=8.5 Hz, 1H), 7.47-7.54(m, 2H), 7.70-7.76 (m, 1H), 10.11 (brs, 1H), 10.54 (brs, 1H).

Example 1-310

MS ESI m/e: 500 (M+H), 498 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.79 (m, 2H), 0.98-1.08 (m, 2H), 2.05(s, 3H), 2.63-2.72 (m, 1H), 2.67 (s, 3H), 4.32 (s, 1H), 5.51 (brs, 1H),7.04-7.12 (m, 1H), 7.35-7.46 (m, 2H), 7.50-7.61 (m, 2H), 7.62-7.67 (m,1H), 7.67-7.72 (m, 1H), 10.16 (s, 1H), 10.75 (s, 1H).

Example 1-311

MS ESI m/e: 666 (M+H), 664 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.71-0.77 (m, 2H), 0.92 (t, J=7.5 Hz, 3H),1.00-1.07 (m, 2H), 1.59-1.71 (m, 2H), 2.62-2.70 (m, 1H), 2.64 (s, 3H),3.09 (t, J=7.4 Hz, 2H), 5.38 (d, J=1.2 Hz, 1H), 7.08-7.14 (m, 1H),7.23-7.37 (m, 3H), 7.41-7.48 (m, 1H), 7.61-7.66 (m, 1H), 7.79-7.84 (m,1H), 10.54 (s, 1H).

Example 1-312

MS ESI m/e: 753, 755 (M+H), 751, 753 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.81-0.89 (m, 2H), 1.14-1.22 (m, 2H),2.70-2.79 (m, 1H), 2.81 (s, 3H), 3.21-3.32 (m, 2H), 3.57-3.68 (m, 2H),5.07 (s, 2H), 5.57-5.67 (m, 1H), 5.65 (d, J=1.1 Hz, 1H), 7.04-7.09 (m,1H), 7.21-7.40 (m, 11H), 7.74-7.80 (m, 1H), 10.34 (brs, 1H).

Example 1-313

MS ESI m/e: 619, 621 (M+H), 617, 619 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.79 (m, 2H), 0.99-1.09 (m, 2H),2.63-2.70 (m, 1H), 2.66 (s, 3H), 3.09-3.19 (m, 2H), 3.37-3.49 (m, 2H),5.36 (d, J=0.9 Hz, 1H), 7.17-7.24 (m, 1H), 7.30-7.39 (m, 2H), 7.47-7.54(m, 3H), 7.73-7.77 (m, 1H), 7.93-8.14 (m, 3H), 10.39 (brs, 1H), 10.52(brs, 1H).

Example 1-314

MS ESI m/e: 703, 705 (M+H), 701, 703 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.78 (m, 2H), 0.82 (t, J=7.2 Hz, 3H),0.99-1.08 (m, 2H), 1.15-1.27 (m, 1H), 1.37-1.47 (m, 2H), 2.01 (t, J=7.5Hz, 2H), 2.62-2.70 (m, 1H), 2.65 (s, 3H), 3.17-3.25 (m, 2H), 3.33-3.43(m, 2H), 5.36 (d, J=1.1 Hz, 1H), 7.11-7.18 (m, 1H), 7.25-7.30 (m, 1H),7.33-7.36 (m, 1H), 7.42-7.54 (m, 3H), 7.72-7.77 (m, 1H), 7.87-7.94 (m,1H), 10.08 (brs, 1H), 10.53 (brs, 1H).

Example 1-315

MS ESI m/e: 659, 661 (M+H), 657, 659 (M−H).

¹H-NMR (DMSO-d, 300 MHz) δ 0.72-0.79 (m, 2H), 1.01-1.09 (m, 2H), 2.14(s, 3H), 2.32-2.39 (m, 4H), 2.60-2.72 (m, 4H), 2.83-2.97 (m, 4H), 5.37(s, 1H), 7.46-7.55 (m, 2H), 7.71-7.87 (m, 5H), 10.51 (s, 1H).

Example 1-316

MS ESI m/e: 646, 648 (M+H), 644, 646 (M−H).

¹H-NMR DMSO-d₆, 300 MHz) δ 0.72-0.79 (m, 2H), 1.01-1.10 (m, 2H),2.60-2.71 (m, 4H), 2.81-2.94 (m, 4H), 3.58-3.67 (m, 4H), 5.38 (s, 1H),7.47-7.55 (m, 2H), 7.71-7.88 (m, 5H), 10.50 (s, 1H).

Example 1-317

MS ESI m/e: 644, 646 (M+H), 642, 644 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 1.00-1.09 (m, 2H),1.32-1.41 (m, 2H), 1.47-1.58 (m, 4H), 2.58-2.73 (m, 4H), 2.82-2.92 (m,4H), 5.37 (s, 1H), 7.46-7.54 (m, 2H), 7.71-7.84 (m, 5H), 10.51 (s, 1H).

Example 1-318

MS ESI m/e: 630, 632 (M+H), 628, 630 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.79 (m, 2H), 1.01-1.10 (m, 2H),1.59-1.69 (m, 4H), 2.58 (s, 3H), 2.63-2.71 (m, 1H), 3.03-3.22 (m, 4H),5.37 (s, 1H), 7.46-7.55 (m, 2H), 7.71-7.82 (m, 3H), 7.87-7.92 (m, 2H),10.51 (s, 1H).

Example 1-319

MS ESI m/e: 666 (M+H), 664 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.79 (m, 2H), 0.99-1.08 (m, 2H), 1.23(d, J=6.6 Hz, 6H), 2.61-2.71 (m, 1H), 2.64 (s, 3H), 5.38 (s, 1H),7.08-7.15 (m, 1H), 7.27-7.38 (m, 3H), 7.39-7.47 (m, 1H), 7.60-7.66 (m,1H), 7.78-7.84 (m, 1H), 9.99 (brs, 1H), 10.54 (s, 1H).

Example 1-320

MS ESI m/e: 564 (M+H), 562 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.79 (m, 2H), 0.92 (t, J=7.3 Hz, 3H),0.99-1.09 (m, 2H), 1.58-1.74 (m, 2H), 2.62-2.72 (m, 1H), 2.66 (s, 3H),3.05-3.14 (m, 2H), 4.32 (s, 1H), 5.51 (s, 1H), 7.09-7.16 (m, 1H),7.24-7.34 (m, 2H), 7.35-7.50 (m, 2H), 7.50-7.61 (m, 2H), 10.04 (brs,1H), 10.73 (s, 1H).

Example 1-321

MS ESI m/e: 564 (M+H), 562 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.79 (m, 2H), 0.99-1.08 (m, 2H), 1.23(d, J=6.6 Hz, 6H), 2.62-2.71 (m, 1H), 2.65 (s, 1H), 3.18-3.30 (m, 1H),4.31 (s, 1H), 5.51 (s, 1H), 7.08-7.14 (m, 1H), 7.26-7.35 (m, 2H),7.35-7.48 (m, 2H), 7.50-7.61 (m, 2H), 10.00 (brs, 1H), 10.73 (s, 1H).

Example 1-322

MS ESI m/e: 655 (M+H), 653 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.79 (m, 2H), 0.99-1.09 (m, 2H),2.61-2.71 (m, 4H), 3.02 (s, 3H), 5.49 (s, 1H), 7.15 (d, J=9.0 Hz, 1H),7.25-7.31 (m, 2H), 7.38-7.49 (m, 2H), 7.74-7.77 (m, 1H), 8.00 (s, 1H),9.99 (brs, 1H), 10.76 (brs, 1H).

Example 1-323

MS ESI m/e: 625, 627 (M+H), 623, 625 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.79 (m, 2H), 0.98-1.09 (m, 2H), 1.70(quint, J=7.2 Hz, 2H), 2.11 (s, 6H), 2.21 (t, J=7.2 Hz, 2H), 2.33 (t,J=7.3 Hz, 2H), 2.62-2.72 (m, 1H), 2.66 (s, 3H), 5.35 (d, J=1.1 Hz, 1H),7.04-7.11 (m, 1H), 7.41 (t, J=8.1 Hz, 1H), 7.45-7.54 (m, 2H), 7.60-7.67(m, 1H), 7.69-7.78 (m, 2H), 10.13 (brs, 1H), 10.54 (brs, 1H).

Example 1-324

MS ESI m/e: 583, 585 (M+H), 581, 583 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.79 (m, 2H), 0.97-1.08 (m, 2H),2.62-2.74 (m, 1H), 2.69 (s, 3H), 2.92 (s, 6H), 5.35 (d, J=1.1 Hz, 1H),6.94-7.01 (m, 1H), 7.34 (t, J=8.1 Hz, 1H), 7.46-7.54 (m, 2H), 7.54-7.61(m, 2H), 7.70-7.77 (m, 1H), 8.51 (brs, 1H), 10.54 (brs, 1H).

Example 1-325

MS ESI m/e: 569, 571 (M+H), 567, 569 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.80 (m, 2H), 0.98-1.09 (m, 2H), 2.63(d, J=4.9 Hz, 3H), 2.65-2.73 (m, 1H), 2.68 (s, 3H), 5.35 (d, J=1. Hz,1H), 6.00-6.08 (m, 1H), 6.89-6.95 (m, 1H), 7.33 (t, J=7.9 Hz, 1H),7.38-7.45 (m, 1H), 7.46-7.52 (m, 2H), 7.52-7.56 (m, 1H), 7.69-7.77 (m,1H), 8.77 (brs, 1H), 10.55 (brs, 1H).

Example 1-326

MS ESI m/e: 465 (M+H), 463 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.80 (m, 2H), 0.99-1.08 (m, 2H), 2.59(s, 3H), 2.62-2.72 (m, 1H), 3.21 (dt, J=4.5, 18.3 Hz, 2H), 5.50 (s, 1H),6.27 (tt, J=4.3, 56.3 Hz, 1H), 7.26-7.34 (m, 2H), 7.34-7.56 (m, 7H),10.55 (brs, 1H).

Example 1-327

MS ESI m/e: 585, 587 (M+H), 583, 585 (M−1).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75 (brs, 2H), 1.03 (m, 2H), 2.68 (s, 4H),3.61 (s, 3H), 5.36 (s, 1H), 7.00-7.10 (m, 1H), 7.38 (t, J=8.1 Hz, 1H),7.45-7.55 (m, 2H), 7.65-7.80 (m, 3H), 9.12 (s, 1H), 9.63 (s, 1H), 10.54(s, 1H).

Example 1-328

MS ESI m/e: 457 (M+H), 455 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.81 (m, 2H), 1.01-1.10 (m, 2H), 2.60(s, 3H), 2.65-2.74 (m, 1H), 5.50 (s, 18H), 7.32 (dd, J=1.9, 8.7 Hz, 1H),7.40-7.56 (m, 6H), 7.82-7.87 (m, 2H), 8.07 (d, J=8.3 Hz, 1H), 10.63(brs, 1H).

Example 1-329

MS ESI m/e: 437 (M+H), 435 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 2.89 (s, 3H), 7.15-7.55 (m, 5H), 10.35 (s,1H).

Example 1-330

MS ESI m/e: 347 (M+H), 345 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 3.41 (s, 3H), 3.53 (s, 3H), 3.56 (s, 3H),7.15-7.23 (m, 2H), 7.32-7.38 (m, 2H), 10.45 (s, 1H).

Example 1-331

MS ESI m/e: 458 (M+H), 456 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.40-0.57 (m, 4H), 1.24-1.37 (m, 1H), 2.81 (s,3H), 2.97 (s, 6H), 3.91 (d, J=7.0 Hz, 2H), 5.61 (s, 1H), 6.70-6.77 (m,2H), 7.10-7.17 (m, 2H), 7.33-7.54 (m, 5H), 10.22 (s, 1H).

Example 1-332

MS ESI m/e: 495 (M+I-H), 496, 493 (M−H), 494.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.70 (s, 3H), 3.84 (s, 3H), 5.88 (s, 1H),7.36-7.55 (m, 10H), 7.46 (d, J=9.0 Hz, 2H), 7.99 (d, J=9.0 Hz, 2H),10.85 (brs, 1H).

Example 1-333

MS ESI m/e: 604, 606 (M+H), 602, 604 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.66-0.74 (m, 2H), 0.98-1.06 (m, 2H), 1.56(s, 3H), 2.60-2.69 (m, 1H), 2.74 (s, 3H), 3.03 (s, 3H), 6.80 (t, J=8.9Hz, 1H), 7.10-7.15 (m, 1H), 7.25-7.36 (m, 3H), 7.46 (t, J=8.0 Hz, 1H),7.59-7.64 (m, 1H), 9.99 (s, 1H), 10.17 (s, 1H).

Example 1-334

MS ESI m/e: 556 (M+H), 554 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.78 (m, 2H), 0.99-1.08 (m, 2H), 2.74(s, 3H), 2.61-2.72 (m, 1H), 2.69-2.79 (m, 2H), 2.98-3.09 (m, 2H), 5.36(s, 1H), 5.92 (brs, 1H), 6.51-6.68 (m, 3H), 7.15-7.20 (m, 1H), 7.49-7.50(m, 2H), 7.72-7.75 (m, 1H), 10.60 (brs, 1H).

Example 1-335

MS ESI m/e: 654 (M+H), 652 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.67-0.81 (m, 2H), 0.96-1.09 (m, 2H), 2.36(s, 3H), 2.61-2.69 (m, 1H), 5.35 (s, 1H), 7.08 (d, J=9.0 Hz, 1H), 7.16(d, J=9.0 Hz, 1H), 7.31-7.39 (m, 2H), 7.48-7.53 (m, 2H), 7.57-7.62 (m,1H), 7.74 (d, J=9.0 Hz, 1H), 8.10 (d, J=9.0 Hz, 1H), 8.77-8.80 (m, 1H),8.88-8.90 (m, 1H), 10.52 (brs, 1H), 10.69 (brs, 1H).

Example 1-336

MS ESI m/e: 532 (M+H), 530 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.80 (m, 2H), 0.99-1.09 (m, 2H), 2.25(s, 3H), 2.61-2.73 (m, 1H), 2.64 (s, 3H), 3.01 (s, 3H), 4.17 (s, 1H),5.27 (s, 1H), 7.14-7.48 (m, 7H), 9.98 (brs, 1H), 10.50 (brs, 1H).

Example 1-337

MS ESI m/e: 552 (M+H), 550 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.68-0.78 (m, 2H), 0.99-1.10 (m, 2H), 2.66(s, 3H), 2.61-2.76 (m, 1H), 3.01 (s, 3H), 4.31 (s, 1H), 5.61 (s, 1H),7.13 (d, J=12.0 Hz, 1H), 7.22-7.32 (m, 2H), 7.41-7.51 (m, 2H), 7.61 (d,J=6.0 Hz, 1H), 7.74 (s, 1H), 9.98 (brs, 1H), 10.90 (brs, 1H).

Example 1-338

MS ESI m/e: 558 (M+H), 556 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.81 (m, 2H), 0.99-1.08 (m, 2H),2.61-2.71 (m, 1H), 2.65 (s, 3H), 3.02 (dt, J=18.8, 3.4 Hz, 2H), 3.02 (s,3H), 4.69 (dt, J=47.1, 3.0 Hz, 2H), 5.28 (s, 1H), 7.10-7.16 (m, 1H),7.17-7.23 (m, 1H), 7.23-7.29 (m, 1H), 7.29-7.39 (m, 2H), 7.41-7.50 (m,2H), 10.00 (brs, 1H), 10.43 (s, 1H).

Example 1-339

MS ESI m/e: 690 (M+H), 688 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.79 (m, 2H), 0.98-1.09 (m, 2H),2.22-2.32 (m, 4H), 2.64 (s, 3H), 2.60-2.71 (m, 3H), 3.25-3.41 (m, 2H),3.41-3.51 (m, 4H), 5.34 (s, 1H), 7.09 (d, J=6.0 Hz, 1H), 7.23-7.35 (m,2H), 7.40-7.51 (m, 3H), 7.73 (d, J=12.0 Hz, 1H), 10.08 (brs, 1H), 10.52(brs, 1H).

Example 1-340

MS ESI m/e: 634 (M+H), 632 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.79 (m, 2H), 0.98-1.09 (m, 2H), 2.22(s, 3H), 2.60-2.69 (m, 1H), 2.63 (s, 3H), 3.01 (s, 3H), 5.14 (s, 1H),7.13 (d, J=9.0 Hz, 2H), 7.22-7.30 (m, 2H), 7.41-7.48 (m, 1H), 7.61-7.64(m, 1H), 7.74 (s, 1H), 9.98 (brs, 1H), 10.32 (brs, 1H).

Example 1-341

MS ESI m/e: 522 (M+H), 520 (M−H).

¹H-NMR (CDCl3, 300 MHz) δ 0.70-0.80 (m, 2H), 0.97-1.09 (m, 2H), 2.06 (s,3H), 2.54 (s, 3H), 2.63-2.72 (m, 1H), 2.66 (s, 3H), 5.23-5.26 (m, 1H),7.05-7.20 (m, 2H), 7.28-7.49 (m, 3H), 7.61-7.73 (m, 2H), 10.17 (brs,1H), 10.41 (brs, 1H).

Example 1-342

MS ESI m/e: 522 (M+H), 520 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.79 (m, 2H), 0.97-1.10 (m, 2H), 2.04(s, 3H), 2.60-2.73 (m, 1H), 2.65 (s, 3H), 3.02 (dt, J=25.2, 2.8 Hz, 2H),4.69 (dt, J=47.1, 3.2 Hz, 2H), 5.27 (s, 1H), 7.02-7.11 (m, 1H),7.16-7.23 (m, 1H), 7.29-7.49 (m, 3H), 7.61-7.71 (m, 2H), 10.16 (brs,1H), 10.44 (brs, 1H).

Example 1-343

MS ESI m/e: 475 (M+H), 473 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.85-0.94 (m, 2H), 1.16-1.24 (m, 2H),2.75-2.83 (m, 1H), 2.82 (s, 3H), 5.54-5.58 (m, 1H), 7.30-7.38 (m, 3H),7.43-7.54 (m, 5H), 7.63-7.69 (m, 1H), 10.28 (brs, 1H).

Example 2-1

MS ESI m/e: 472 (M+H), 470 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 2.68 (s, 3H), 7.34-7.39 (m, 2H), 7.41-7.61(m, 10H), 7.80-7.87 (m, 2H), 11.34 (s, 1H).

Example 2-2

MS ES m/e: 592 (M+H), 590 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.82 (m, 2H), 1.01-1.13 (m, 2H),2.64-2.75 (m, 1H), 2.67 (s, 3H), 3.05 (s, 3H), 7.19-7.27 (m, 1H),7.27-7.34 (m, 1H), 7.35-7.39 (m, 1H), 7.45-7.54 (m, 2H), 7.71 (dd,J=3.0, 12.0 Hz, 1H), 8.51 (t, J=9.0 Hz, 1H), 10.05 (s, 1H), 11.61 (d,J=3.0 Hz, 1H).

Example 3-1

MS ESI m/e: 493, 495 (M+H), 491, 493 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.77-0.82 (m, 2H), 1.09-1.15 (m, 2H), 1.36 (s,3H), 2.72-2.74 (m, 1H), 3.20 (s, 3H), 6.86 (d, 2H), 7.28-7.32 (m, 2H),7.34-7.51 (m, 5H), 11.36 (s, 1H).

Example 3-2

MS ESI m/e: 479, 481 (M+H), 477, 479 (M−H).

¹H-NMR (CDCl₃, 400 MHz) δ 0.83-0.90 (m, 2H), 1.10-1.18 (m, 2H),2.67-2.76 (m, 1H), 3.11 (s, 3H), 5.00 (s, 1H), 7.02 (d, J=8.6 Hz, 2H),7.10-7.15 (m, 2H), 7.19-7.25 (m, 1H), 7.34-7.41 (m, 2H), 7.63-7.70 (m,2H), 11.71 (s, 1H).

Example 3-3

MS ESI m/e: 479, 481 (M+H), 477, 479 (M−H).

¹H-NMR (CDCl₃, 300 MHz) δ 0.83-0.92 (m, 2H), 1.09-1.19 (m, 2H),2.67-2.78 (m, 1H), 3.13 (s, 3H), 5.06 (s, 1H), 6.87-6.94 (m, 2H),7.21-7.28 (m, 2H), 7.45-7.60 (m, 5H), 11.68 (s, 1H).

Example 3-4

MS ESI m/e: 604 (M+H), 606, 602 (M−H), 604.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.65-0.69 (m, 2H), 0.93-0.98 (m, 2H), 1.25(s, 3H), 2.59-2.64 (m, 1H), 3.01 (s, 3H), 3.08 (s, 3H), 7.08-7.13 (m,2H), 7.21-7.25 (m, 2H), 7.39-7.43 (m, 2H), 7.70-7.74 (m, 1H), 9.90 (brs,1H), 11.09 (brs, 1H).

Example 3-5

MS ESI m/e: 618 (M+H), 620, 616 (M−H), 618.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.69 (m, 2H), 0.92-0.98 (m, 2H), 1.19(t, J=9.8 Hz, 3H), 1.24 (s, 3H), 2.58-2.64 (m, 1H), 3.11 (q, J=9.8 Hz,2H), 3.08 (s, 3H), 7.07-7.13 (m, 2H), 7.21-7.25 (m, 2H), 7.37-7.42 (m,2H), 7.70-7.74 (m, 2H), 9.95 (brs, 1H), 11.09 (brs, 1H).

Example 3-6

MS ESI m/e: 604 (M+H), 606, 602 (M−H), 604.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.69 (m, 2H), 0.92-0.99 (m, 2H), 1.25(s, 3H), 2.04 (s, 3H), 2.58-2.66 (m, 1H), 3.08 (s, 3H), 7.01-7.13 (m,2H), 7.33-7.43 (m, 2H), 7.58-7.60 (m, 2H), 7.70-7.74 (m, 1H), 10.10(brs, 1H), 11.09 (brs, 1H).

Example 3-7

MS ESI m/e: 652 (M+H), 650 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.72 (m, 2H), 0.91-1.01 (m, 2H), 1.25(s, 3H), 2.57-2.67 (m, 1H), 3.01 (s, 3H), 3.08 (s, 3H), 6.92 (t, J=9.0Hz, 1H), 7.09-7.14 (m, 1H), 7.20-7.26 (m, 2H), 7.37-7.45 (m, 1H),7.52-7.58 (m, 1H), 7.79 (dd, J=1.8, 9.0 Hz, 1H), 9.89 (s, 1H), 11.08 (s,1H).

Example 3-8

MS ESI m/e: 550 (M+H), 548 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.71 (m, 2H), 0.90-1.01 (m, 2H), 1.26(s, 3H), 2.56-2.66 (m, 1H), 3.01 (s, 3H), 3.10 (s, 3H), 4.30 (s, 1H),7.05-7.16 (m, 2H), 7.20-7.27 (m, 2H), 7.32 (dd, J=1.7, 9.0 Hz, 1H),7.37-7.45 (m, 1H), 7.52 (dd, J=1.7, 12.0 Hz, 1H), 9.90 (s, 1H), 11.10(s, 1H).

Example 3-9

MS ESI m/e: 639 (M+H), 638, 637 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.65-0.73 (m, 2H), 0.93-0.98 (m, 2H), 1.26(s, 3H), 2.58-2.65 (m, 1H), 3.05 (s, 3H), 3.08 (s, 3H), 7.11 (dd, J=10.1Hz, 13.0 Hz, 1H), 7.32 (d, J=11.6 Hz, 1H), 7.42 (d, J=10.1 Hz, 1H), 7.48(s, 1H), 7.63 (d, J=11.6 Hz, 1H), 7.72 (d, J=13.0 Hz, 1H), 9.65 (brs,1H), 11.08 (brs, 1H).

Example 4-1

MS ESI m/e: 616 (M+H), 614 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.63-0.70 (m, 2H), 0.91-1.00 (m, 2H), 1.25(s, 3H), 2.04 (s, 3H), 2.58-2.66 (m, 1H), 3.07 (s, 3H), 6.92 (t, J=8.8Hz, 1H), 7.00-7.05 (m, 1H), 7.36 (t, J=8.2 Hz, 1H), 7.52-7.63 (m, 3H),7.79 (dd, J=2.0, 10.4 Hz, 1H), 10.10 (s, 1H), 11.08 (s, 1H).

Example 4-2

MS ESI m/e: 666 (M+H), 664 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.71 (m, 2H), 0.91-1.01 (m, 2H), 1.19(t, J=7.2 Hz, 3H), 1.24 (s, 3H), 2.56-2.67 (m, 1H), 3.08 (s, 3H), 3.11(q, J=7.2 Hz, 2H), 6.92 (t, J=8.7 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H),7.21-7.28 (m, 2H), 7.40 (t, J=8.3 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.79(dd, J=1.8, 10.5 Hz, 1H), 9.94 (s, 1H), 11.08 (s, 1H).

Example 4-3

MS ESI m/e: 514 (M+H), 512 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.63-0.70 (m, 2H), 0.91-0.99 (m, 2H), 1.26(s, 3H), 2.04 (s, 3H), 2.58-2.66 (m, 1H), 3.10 (s, 3H), 4.30 (s, 1H),7.01-7.06 (m, 1H), 7.09 (t, J=8.4 Hz, 1H), 7.31 (dd, J=1.6, 8.4 Hz, 1H),7.36 (t, J=7.8 Hz, 1H), 7.52 (dd, J=1.6, 11.6 Hz, 1H), 7.57-7.63 (m,2H), 10.10 (s, 1H), 11.10 (s, 1H)

Example 4-4

MS ESI m/e: 568, 570 (M+H), −566, 568 (M−H)

¹H-NMR (DMSO-d₆, 300 MHz) 0.61-0.65 (m, 2H), 0.90-0.95 (m, 2H), 1.20 (s,3H), 2.04 (s, 3H), 2.56-2.61 (m, 1H), 3.04 (s, 3H), 7.07 (dd, J=8.6,10.7 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 7.38 (d, J=10.7 Hz, 1H), 7.60 (d,J=8.8 Hz, 2H), 7.69 (d, J=8.6 Hz, 1H), 10.07 (s, 1H), 11.05 (s, 1H)

Example 4-5

MS ESI m/e: 556, 558 (M+1).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.63-0.67 (m, 2H), 0.91-0.96 (m, 2H), 1.17(s, 3H), 2.56-2.62 (m, 1H), 3.05 (s, 3H), 7.11 (dd, J=8.6, 10.4 Hz, 1H),7.40 (d, J-8.6 Hz, 1H), 7.66 (d, J=9.3 Hz, 2H), 7.69 (dd, J=2.1, 10.4Hz, 1H), 8.30 (d, J=9.3 Hz, 2H), 10.94 (s, 1H)

Example 4-6

MS ESI m/e: 564 (M+H), 562 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.64-0.70 (m, 2H), 0.92-0.99 (m, 2H), 1.19(t, J=7.4 Hz, 3H), 1.25 (s, 3H), 2.57-2.65 (m, 1H), 3.10 (s, 3H), 3.11(q, J=7.4 Hz, 2H), 4.31 (s, 1H), 7.06-7.12 (m, 2H), 7.22-7.27 (m, 2H),7.32 (dd, J=1.6, 8.0 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.52 (dd, J=1.6,11.6 Hz, 1H), 9.95 (s, 1H), 11.10 (s, 1H).

Example 4-7

MS ESI m/e: 490 (M+H), 488 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.64-0.71 (m, 2H), 0.91-0.99 (m, 2H), 1.25(s, 3H), 2.04 (s, 3H), 2.60-2.67 (m, 1H), 3.05 (s, 3H), 7.02-7.06 (m,1H), 7.13-7.19 (m, 1H), 7.20-7.29 (m, 2H), 7.33-7.41 (m, 2H), 7.57-7.63(m, 2H), 10.10 (s, 1H), 11.23 (s, 1H).

Example 4-8

MS ESI m/e: 604, 606 (M+H), 602, 604 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.69 (m, 2H), 0.92-0.99 (m, 2H), 1.23(s, 3H), 2.57-2.67 (m, 1H), 3.04 (s, 3H), 3.07 (s, 3H), 7.08-7.14 (m,1H), 7.26 (d, J=9.0 Hz, 2H), 7.34 (d, J=9.0 Hz, 2H), 7.39-7.44 (m, 1H),7.70-7.75 (m, 1H), 9.96 (s, 1H), 11.08 (s, 1H)

Example 4-9

MS ESI m/e: 518 (M+H), 516 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.64-0.71 (m, 2H), 0.92-1.00 (m, 2H), 1.19(t, J=7.6 Hz, 3H), 1.24 (s, 3H), 2.04 (s, 3H), 2.59-2.67 (m, 1H), 2.62(q, J=7.6 Hz, 2H), 3.03 (s, 3H), 7.01-7.11 (m, 3H), 7.23 (d, J=11.6 Hz,1H), 7.36 (t, J=8.2 Hz, 1H), 7.56-7.63 (m, 2H), 10.10 (s, 1H), 11.23 (s,1H).

Example 4-10

MS ESI m/e: 603, 605 (M+H), 601, 603 (M−H).

¹H-NMR (CDCl3, 300 MHz) δ 0.77-0.84 (m, 2H), 1.11-1.18 (m, 2H), 1.32 (t,J=7.3 Hz, 3H), 1.33 (s, 3H), 2.70-2.78 (m, 1H), 3.15 (q, J=7.5 Hz, 2H),3.20 (s, 3H), 6.89 (t, J=8.3 Hz, 1H), 7.28-7.32 (m, 1H), 7.36 (dd,J=2.3, 9.8 Hz, 1H), 7.60-7.69 (m, 2H), 7.86-7.93 (m, 2H), 11.28 (s, 1H).

Example 4-11

MS ESI m/e: 516 (M+H), 514 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.64-0.71 (m, 2H), 0.92-1.00 (m, 2H), 1.25(s, 3H), 2.04 (s, 3H), 2.59-2.67 (m, 1H), 3.07 (s, 3H), 5.32 (d, J=11.1Hz, 1H), 5.89 (d, J=17.6 Hz, 1H), 6.73 (dd, J=10.9, 17.6 Hz, 1H),7.01-7.06 (m, 1H), 7.11 (t, J=8.6 Hz, 1H), 7.28-7.33 (m, 1H), 7.33-7.40(m, 1H), 7.51-7.57 (m, 1H), 7.57-7.63 (m, 2H), 10.10 (s, 1H), 11.22 (s,1H).

Example 4-12

MS ESI m/e: 729 (M+H), 727 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.65-0.68 (m, 2H), 0.83 (t, J=7.3 Hz, 3H),0.93-0.97 (m, 2H), 1.23-1.26 (m, 5H), 1.40-1.50 (m, 2H), 2.04 (t, J=7.5Hz, 2H), 2.48-2.50 (m, 2H), 2.59-2.64 (m, 1H), 3.08 (s, 3H), 3.28-3.33(m, 2H), 6.92 (t, J=8.7 Hz, 1H), 7.03 (d, J=7.9 Hz, 1H), 7.36 (t, J=8.1Hz, 1H), 7.56-7.59 (m, 2H), 7.64-7.66 (m, 1H), 7.79 (dd, J=10.4, 1.7 Hz,1H), 7.90 (t, J=5.7 Hz, 1H), 10.10 (s, 1H), 11.08 (s, 1H).

Example 4-13

MS ESI m/e: 603 (M+H), 601 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.66-0.69 (m, 2H), 0.83 (t, J=7.2 Hz, 3H),0.93-0.98 (m, 2H), 1.17-1.29 (m, 5H), 1.40-1.50 (m, 2H), 2.04 (t, J=7.3Hz, 2H), 2.47-2.51 (m, 2H), 2.61-2.65 (m, 1H), 3.05 (s, 3H), 3.29-3.33(m, 2H), 7.04 (d, J=9.0 Hz, 1H), 7.19-7.34 (m, 5H), 7.59 (d, J=8.7 Hz,1H), 7.66 (s, 1H), 7.91 (t, J=5.3 Hz, 1H), 10.10 (s, 1H), 11.23 (s, 1H).

Example 4-14

MS ESI m/e: 685 (M+H), 683 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.70 (m, 2H), 0.82 (t, J=7.3 Hz, 3H),0.90-0.98 (m, 2H), 1.14-1.28 (m, 4H), 1.25 (s, 3H), 1.37-1.49 (m, 2H),1.45 (s, 6H), 2.04 (t, J=7.3 Hz, 2H), 2.58-2.65 (m, 1H), 3.07 (s, 3H),3.27-3.34 (m, 2H), 5.49 (brs, 1H), 6.99-7.11 (m, 2H), 7.18-7.25 (m, 1H),7.31-7.42 (m, 2H), 7.55-7.67 (m, 2H), 7.85-7.93 (m, 1H), 10.09 (s, 1H),11.14 (s, 1H).

Example 4-15

MS ESI m/e: 590 (M+H), 588 (M−H).

¹H-NMR (CDCl3, 300 MHz) δ 1.42 (s, 3H), 2.16 (s, 3H), 3.21 (s, 3H), 3.37(s, 3H), 6.69 (t, J=8.3 Hz, 1H), 7.04-7.10 (m, 1H), 7.31-7.55 (m, 5H),7.70 (s, 1H), 11.41 (s, 1H).

Example 4-16

MS ESI m/e: 626 (M+H), 624 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.26 (s, 3H), 3.01 (s, 3H), 3.09 (s, 3H),3.21 (s, 3H), 6.93 (t, J=8.3 Hz, 1H), 7.11-7.15 (m, 1H), 7.20-7.28 (m,2H), 7.42 (t, J=8.3 Hz, 1H), 7.52-7.57 (m, 1H), 7.76-7.81 (m, 1H), 9.94(br, 1H), 11.21 (br, 1H).

Example 4-17

MS ESI m/e: 630 (M+H), 628 (M−H).

¹H-NMR (CDCl3, 300 MHz) δ 0.75-0.81 (m, 2H), 1.05-1.15 (m, 5H), 1.41 (s,3H), 2.15 (s, 3H), 2.68-2.77 (m, 1H), 3.90-4.00 (m, 2H), 6.72 (t, J=8.3Hz, 1H), 6.97-7.03 (m, 1H), 7.30-7.54 (m, 5H), 7.65-7.69 (m, 1H), 11.07(s, 1H).

Example 4-18

MS ESI m/e: 666 (M+H), 664 (M−H).

¹H-NMR (CDCl3, 300 MHz) δ 0.75-0.81 (m, 2H), 1.06-1.15 (m, 5H), 1.39 (s,3H), 2.68-2.76 (m, 1H), 3.02 (s, 3H), 3.90-4.00 (m, 2H), 6.74 (t, J=8.3Hz, 1H), 6.93-6.99 (m, 1H), 7.07-7.13 (m, 1H), 7.20-7.26 (m, 2H),7.38-7.54 (m, 3H), 11.07 (s, 1H).

Example 4-19

MS ESI m/e: 654 (M+H), 652 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.13 (t, J=6.8 Hz, 3H), 1.20 (t, J=7.2 Hz,3H), 1.25 (s, 3H), 3.08 (s, 3H), 3.12 (q, J=7.4 Hz, 2H), 3.87 (d, J=7.1Hz, 2H), 6.94 (t, J=8.6 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.4Hz, 1H), 7.29 (s, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H),7.79 (d, J=10.5 Hz, 1H), 9.98 (s, 1H), 11.24 (s, 1H).

Example 4-20

MS ESI m/e: 640 (M+H), 638 (M−H).

¹H-NMR (DMSO-ds, 300 MHz) δ 1.13 (t, J=6.8 Hz, 3H), 1.26 (s, 3H), 3.02(s, 3H), 3.09 (s, 3H), 3.88 (q, J=6.8 Hz, 2H), 6.95 (t, J=8.5 Hz, 1H),7.11-7.18 (m, 1H), 7.21-7.30 (m, 2H), 7.43 (t, J=7.7 Hz, 1H), 7.55 (d,J=9.0 Hz, 1H), 7.76-7.82 (m, 1H), 9.94 (brs, 1H), 11.24 (brs, 1H).

Example 4-21

MS ESI m/e: 604 (M+H), 602 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.13 (t, J=6.8 Hz, 3H), 1.26 (s, 3H), 2.04(s, 3H), 3.08 (s, 3H), 3.87 (q, J=7.5 Hz, 2H), 6.94 (t, J=8.5 Hz, 1H),7.05-7.11 (m, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.51-7.60 (m, 2H), 7.65-7.71(m, 1H), 7.78 (d, J=10.2 Hz, 1H), 10.10 (brs, 1H), 11.23 (brs, 1H).

Example 4-22

MS ESI m/e: 666 (M+H), 664 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.47 (t, J=7.2 Hz, 3H), 0.63-0.69 (m, 2H),0.90-0.97 (m, 2H), 1.76-1.94 (m, 2H), 2.57-2.63 (m, 1H), 3.00 (s, 3H),3.07 (s, 3H), 6.93 (t, J=8.8 Hz, 1H), 7.12-7.16 (m, 1H), 7.23-7.30 (m,2H), 7.42 (t, J=8.0 Hz, 1H), 7.53-7.58 (m, 1H), 7.79 (dd, J=1.6, 10.0Hz, 1H), 9.91 (s, 1H), 11.07 (s, 1H).

Example 4-23

MS ESI m/e: 680 (M+H), 678 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.47 (t, J=7.4 Hz, 3H), 0.61-0.70 (m, 2H),0.89-0.98 (m, 2H), 1.20 (t, J=7.4 Hz, 3H), 1.74-1.95 (m, 2H), 2.55-2.65(m, 1H), 3.07 (s, 3H), 3.11 (q, J=7.4 Hz, 2H), 6.92 (t, J=8.6 Hz, 1H),7.11 (d, J=7.8 Hz, 1H), 7.22-7.31 (m, 2H), 7.40 (t, J=7.9 Hz, 1H), 7.56(d, J=8.7 Hz, 1H), 7.79 (d, J=10.2 Hz, 1H), 9.97 (s, 1H), 11.07 (s, 1H).

Example 4-24

MS ESI m/e: 630 (M+H), 628 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.47 (t, J=7.2 Hz, 3H), 0.60-0.69 (m, 2H),0.87-0.98 (m, 2H), 1.79-1.93 (m, 2H), 2.04 (s, 3H), 2.56-2.66 (m, 1H),3.07 (s, 3H), 6.92 (t, J=8.6 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.37 (t,J=8.1 Hz, 1H), 7.53-7.69 (m, 3H), 7.79 (d, J=10.2 Hz, 1H), 10.09 (s,1H), 11.07 (s, 1H).

Example 4-25

MS ESI m/e: 554 (M+H), 552 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.73 (m, 2H), 0.91-1.01 (m, 2H), 1.19(t, J=7.5 Hz, 3H), 1.24 (s, 3H), 2.57-2.68 (m, 1H), 2.62 (q, J=7.4 Hz,2H), 3.01 (s, 3H), 3.03 (s, 3H), 7.03-7.15 (m, 3H), 7.19-7.27 (m, 3H),7.41 (t, J=8.1 Hz, 1H), 9.89 (s, 1H), 11.24 (s, 111H).

Example 4-26

MS ESI m/e: 568 (M+H), 566 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.73 (m, 2H), 0.91-1.01 (m, 2H), 1.18(t, J=7.5 Hz, 3H), 1.19 (t, J=7.2 Hz, 3H), 1.23 (s, 3H), 2.57-2.68 (m,1H), 2.62 (q, J=7.5 Hz, 2H), 3.03 (s, 3H), 3.11 (q, J=7.2 Hz, 2H),7.03-7.13 (m, 3H), 7.19-7.27 (m, 3H), 7.40 (t, J=8.1 Hz, 1H), 9.94 (s,1H), 11.24 (s, 1H).

Example 4-27

MS ESI m/e: 528 (M+H), 526 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.48 (t, J=7.4 Hz, 3H), 0.60-0.70 (m, 2H),0.88-0.98 (m, 2H), 1.77-1.92 (m, 2H), 2.04 (s, 3H), 2.55-2.66 (m, 1H),3.10 (s, 3H), 4.30 (s, 1H), 7.04-7.14 (m, 2H), 7.28-7.41 (m, 2H), 7.52(d, J=11.7 Hz, 1H), 7.58-7.68 (m, 2H), 10.09 (s, 1H), 11.08 (s, 1H).

Example 4-28

MS ESI m/e: 564 (M+H), 562 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.48 (t, J=7.2 Hz, 3H), 0.63-0.69 (m, 2H),0.90-0.97 (m, 2H), 1.78-1.93 (m, 2H), 2.56-2.64 (m, 1H), 3.01 (s, 3H),3.10 (s, 3H), 4.31 (s, 1H), 7.09 (t, J=8.4 Hz, 1H), 7.13-7.17 (m, 1H),7.23-7.34 (m, 3H), 7.42 (t, J=8.0 Hz, 1H), 7.52 (dd, J=2.0, 11.6 Hz,1H), 9.92 (s, 1H), 11.08 (s, 1H).

Example 4-29

MS ESI m/e: 578 (M+M), 576 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.47 (t, J=7.1 Hz, 3H), 0.61-0.70 (m, 2H),0.88-0.98 (m, 2H), 1.20 (t, J=7.2 Hz, 3H), 1.75-1.95 (m, 2H), 2.55-2.64(m, 1H), 3.10 (s, 3H), 3.11 (q, J=7.2 Hz, 2H), 4.30 (s, 1H), 7.04-7.14(m, 2H), 7.23-7.35 (m, 3H), 7.40 (t, J=7.8 Hz, 1H), 7.52 (d, J=11.4 Hz,1H), 9.97 (s, 1H), 11.08 (s, 1H).

Example 4-30

MS ESI m/e: 532 (M+H), 530 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) 0.46 (t, J=7.4 Hz, 3H), 0.64-0.70 (m, 2H),0.90-0.97 (m, 2H), 1.19 (t, J=7.6 Hz, 3H), 1.80-1.90 (m, 2H), 2.04 (s,3H), 2.57-2.67 (m, 1H), 2.63 (q, J=7.6 Hz, 2H), 3.02 (s, 3H), 7.04-7.13(m, 3H), 7.23 (d, J=12.0 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.61 (d, J=7.6Hz, 1H), 7.64 (t, J=2.0 Hz, 1H), 10.09 (s, 1H), 11.24 (s, 1H).

Example 4-31

MS ESI m/e: 568 (M+H), 566 (M−H).

¹H-NMR (DMSO-d, 400 MHz) δ 0.47 (t, J=7.2 Hz, 3H), 0.63-0.71 (m, 2H),0.90-0.98 (m, 2H), 1.19 (t, J=7.4 Hz, 3H), 1.74-1.96 (m, 2H), 2.57-2.67(m, 1H), 2.63 (q, J=7.4 Hz, 2H), 3.01 (s, 3H), 3.02 (s, 3H), 7.06-7.11(m, 2H), 7.12-7.17 (m, 1H), 7.20-7.30 (m, 3H), 7.42 (t, J=8.0 Hz, 1H),9.91 (s, 1H), 11.24 (s, 1H).

Example 4-32

MS ESI m/e: 582 (M+H), 580 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.46 (t, J=7.2 Hz, 3H), 0.64-0.70 (m, 2H),0.90-0.98 (m, 2H), 1.19 (t, J=7.6 Hz, 3H), 1.20 (t, J=7.6 Hz, 3H),1.75-1.93 (m, 2H), 2.58-2.68 (m, 1H), 2.63 (q, J=7.6 Hz, 2H), 3.02 (s,3H), 3.10 (q, J=7.6 Hz, 2H), 7.05-7.14 (m, 3H), 7.20-7.31 (m, 3H), 7.40(t, J=8.0 Hz, 1H), 9.97 (s, 1H), 11.23 (s, 1H).

Example 4-33

MS ESI m/e: 681 (M+H), 679 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.61-0.69 (m, 2H), 0.90-1.00 (m, 2H), 1.22(s, 3H), 2.52-2.63 (m, 1H), 2.67 (s, 6H), 3.06 (s, 3H), 6.88-6.94 (m,1H), 7.02-7.09 (m, 1H), 7.18-7.21 (m, 2H), 7.31-7.39 (m, 1H), 7.51-7.56(m, 1H), 7.75-7.81 (m, 1H), 10.01 (brs, 1H), 11.06 (brs, 1H)

Example 4-34

MS ESI m/e: 723 (M+H), 721 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.61-0.70 (m, 2H), 0.90-0.99 (m, 2H), 1.24(s, 3H), 2.55-2.64 (m, 1H), 3.06 (s, 3H), 2.99-3.10 (m, 4H), 3.43-3.53(m, 4H), 6.88-6.92 (m, 1H), 7.05-7.09 (m, 2H), 7.14-7.22 (m, 1H),7.31-7.40 (m, 1H), 7.51-7.59 (m, 1H), 7.75-7.81 (m, 1H), 10.21 (brs,1H), 11.08 (brs, 1H).

Example 4-35

MS ESI m/e: 519 (M+H), 517 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.71 (m, 2H), 0.92-1.00 (m, 2H), 1.26(s, 3H), 2.59-2.67 (m, 1H), 2.73 (t, J=7.0 Hz, 2H), 3.02-3.12 (m, 2H),3.05 (s, 3H), 7.04-7.43 (m, 6H), 7.58-7.63 (m, 1H), 7.67 (s, 1H),7.77-7.88 (m, 3H), 10.39 (s, 1H), 11.23 (s, 1H).

Example 4-36

MS ESI m/e: 645 (M+H), 643 (M−H).

¹H-NMR (DMSO-d, 300 MHz) δ 0.62-0.70 (m, 2H), 0.92-0.98 (m, 2H), 1.26(s, 3H), 2.59-2.66 (m, 1H), 2.72 (t, J=7.2 Hz, 2H), 3.03-3.13 (m, 2H),3.08 (s, 3H), 6.93 (t, J=8.4 Hz, 1H), 7.03-7.08 (m, 1H), 7.39 (t, J=8.4Hz, 1H), 7.53-7.68 (m, 3H), 7.72-7.85 (m, 4H), 10.37 (s, 1H), 11.08 (s,1H).

Example 4-37

MS ESI m/e: 650 (M+H), 648 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.69 (m, 2H), 0.92-0.99 (m, 2H), 1.31(s, 3H), 2.06 (s, 3H), 2.57-2.64 (m, 1H), 3.08 (s, 3H), 6.93 (dd, J=9.3,11.1 Hz, 1H), 7.19 (s, 1H), 7.46 (s, 1H), 7.55 (d, J=9.3 Hz, 1H), 7.79(d, J=11.1 Hz, 1H), 7.83 (s, 1H), 10.27 (s, 1H), 11.03 (s, 1H)

Example 4-38

MS ESI m/e: 564 (M+H), 562 (M−H).

¹H-NMR (CDCl3, 300 MHz) δ 0.75-0.81 (m, 2H), 1.06-1.16 (m, 5H), 1.40 (s,3H), 2.69-2.76 (m, 1H), 3.03 (s, 3H), 3.13 (s, 1H), 3.92-4.01 (m, 2H),6.77-6.84 (m, 1H), 6.92 (t, J=8.1 Hz, 1H), 7.08-7.13 (m, 1H), 7.18-7.33(m, 4H), 7.42 (t, J=8.1 Hz, 1H), 11.11 (s, 1H).

Example 4-39

MS ESI m/e: 568 (M+H), 566 (M−H).

¹H-NMR (CDCl3, 300 MHz) δ 0.75-0.83 (m, 2H), 1.02 (t, J=7.0 Hz, 3H),1.07-1.15 (m, 2H), 1.24 (t, J=7.7 Hz, 3H), 1.38 (s, 3H), 2.60-2.76 (m,3H), 3.02 (s, 3H), 3.90-4.00 (m, 2H), 6.77 (s, 1H), 6.94-7.03 (m, 3H),7.08-7.13 (m, 1H), 7.19-7.27 (m, 2H), 7.41 (t, J=7.7 Hz, 1H), 11.19 (s,1H).

Example 4-40

MS ESI m/e: 552 (M+H), 550 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.13 (t, J=6.9 Hz, 3H), 1.20 (t, J=7.3 Hz,3H), 1.26 (s, 3H), 3.11 (s, 3H), 3.12 (q, J=7.4 Hz, 2H), 3.87 (q, J=7.1Hz, 2H), 4.30 (s, 1H), 7.05-7.15 (m, 2H), 7.20-7.35 (m, 3H), 7.41 (t,J=8.0 Hz, 1H), 7.52 (d, J=11.6 Hz, 1H), 9.99 (s, 1H), 11.25 (s, 1H).

Example 4-41

MS ESI m/e: 556 (M+H), 554 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) 1.10-1.25 (m, 12H), 2.62 (q, J=7.6 Hz, 2H),3.03 (s, 3H), 3.12 (q, J=7.3 Hz, 2H), 3.88 (q, J=6.9 Hz, 2H), 7.05-7.15(m, 3H), 7.20-7.30 (m, 3H), 7.41 (t, J=8.0 Hz, 1H), 9.98 (s, 1H), 11.41(s, 1H).

Example 4-42

MS ESI m/e: 538 (M+H), 536 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.13 (t, J=7.2 Hz, 3H), 1.27 (s, 3H), 3.03(s, 3H), 3.11 (s, 3H), 3.87 (q, J=6.8 Hz, 2H), 4.30 (s, 1H), 7.05-7.18(m, 2H), 7.20-7.35 (m, 3H), 7.43 (t, J=7.9 Hz, 1H), 7.52 (d, J=11.3 Hz,1H), 9.94 (brs, 1H), 11.25 (brs, 1H).

Example 4-43

MS ESI m/e: 502 (M+H), 500 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.13 (t, J=7.0 Hz, 3H), 1.27 (s, 3H), 2.05(s, 3H), 3.11 (s, 3H), 3.87 (q, J=7.1 Hz, 2H), 4.30 (s, 1H), 7.04-7.15(m, 2H), 7.28-7.34 (m, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.49-7.60 (m, 2H),7.66-7.70 (m, 1H), 10.10 (brs, 1H), 11.24 (brs, 1H).

Example 4-44

MS ESI m/e: 542 (M+H), 540 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.14 (t, J=7.2 Hz, 3H), 1.19 (t, J=7.5 Hz,3H), 1.25 (s, 3H), 2.63 (q, J=7.5 Hz, 2H), 3.02 (s, 3H), 3.03 (s, 3H),3.89 (q, J=7.0 Hz, 2H), 7.04-7.18 (m, 3H), 7.20-7.30 (m, 3H), 7.42 (t,J=8.1 Hz, 1H), 9.93 (brs, 1H), 11.41 (brs, 1H).

Example 4-45

MS ESI m/e: 506 (M+H), 504 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.14 (t, J=6.2 Hz, 3H), 1.19 (t, J=7.5 Hz,3H), 1.25 (s, 3H), 2.05 (s, 3H), 2.63 (q, J=7.5 Hz, 2H), 3.03 (s, 3H),3.89 (q, J=6.8 Hz, 2H), 7.04-7.15 (m, 3H), 7.23 (d, J=12.0 Hz, 1H), 7.37(t, J=8.1 Hz, 1H), 7.53-7.60 (m, 1H), 7.65-7.70 (m, 1H), 10.10 (brs,1H), 11.41 (brs, 1H).

Example 4-46

MS ESI m/e: 528 (M+H), 526 (M−H).

¹H-NMR (CDCl3, 300 MHz) δ 0.75-0.82 (m, 2H), 1.06-1.16 (m, 5H), 1.42 (s,3H), 2.17 (s, 3H), 2.68-2.78 (m, 1H), 3.13 (s, 1H), 3.92-4.01 (m, 2H),6.90 (t, J=7.9 Hz, 1H), 6.99-7.06 (m, 1H), 7.22-7.46 (m, 5H), 7.63-7.68(m, 1H), 11.10 (s, 1H).

Example 4-47

MS ESI m/e: 532 (M+H), 530 (M−H).

¹H-NMR (CDCl3, 300 MHz) δ 0.75-0.83 (m, 2H), 1.02 (t, J=7.0 Hz, 3H),1.08-1.16 (m, 2H), 1.24 (t, J=7.5 Hz, 3H), 1.40 (s, 3H), 2.16 (s, 3H),2.61-2.77 (m, 3H), 3.91-4.00 (m, 2H), 6.93-7.05 (m, 4H), 7.26-7.48 (m,3H), 7.59-7.64 (m, 1H), 11.19 (s, 1H).

Example 4-48

MS ESI m/e: 488 (M+H), 486 (M−H).

¹H-NMR (CDCl3, 300 MHz) δ 1.42 (s, 3H), 2.15 (s, 3H), 3.13 (s, 1H), 3.23(s, 3H), 3.38 (s, 3H), 6.86 (t, J=8.7 Hz, 1H), 7.03-7.10 (m, 1H),7.22-7.41 (m, 5H), 7.70 (s, 1H), 11.46 (s, 1H).

Example 4-49

MS ESI m/e: 524 (M+H), 522 (M−H).

¹H-NMR (CDCl3, 300 MHz) δ 1.41 (s, 3H), 3.04 (s, 3H), 3.14 (s, 1H), 3.23(s, 3H), 3.38 (s, 3H), 6.75 (s, 1H), 6.89 (t, J=8.5 Hz, 1H), 7.11-7.17(m, 1H), 7.18-7.33 (m, 4H), 7.43 (t, J=8.1 Hz, 1H), 11.47 (s, 1H).

Example 4-50

MS ESI m/e: 492 (M+H), 490 (M−H).

¹H-NMR (CDCl3, 300 MHz) δ 1.24 (t, J=7.5 Hz, 3H), 1.41 (s, 3H), 2.15 (s,3H), 2.65 (q, J=7.7 Hz, 2H), 3.18 (s, 3H), 3.38 (s, 3H), 6.88-7.11 (m,4H), 7.32-7.46 (m, 3H), 7.63-7.69 (m, 1H), 11.45 (s, 1H).

Example 4-51

MS ESI m/e: 528 (M+H), 526 (M−H).

¹H-NMR (CDCL3, 300 MHz) δ 1.24 (t, J=7.5 Hz, 3H), 1.39 (s, 3H), 2.65 (q,J=7.3 Hz, 2H), 3.03 (s, 3H), 3.18 (s, 3H), 3.38 (s, 3H), 6.84 (s, 1H),6.90-7.03 (m, 3H), 7.11-7.17 (m, 1H), 7.19-7.30 (m, 2H), 7.42 (t, J=8.1Hz, 1H), 11.46 (s, 1H).

Example 4-52

MS ESI m/e: 528 (M+H), 526 (M−H).

¹H-NMR (DMSO-dc, 400 MHz) δ 0.64-0.70 (m, 2H), 0.91-0.99 (m, 2H), 1.25(s, 3H), 2.04 (s, 3H), 2.05 (s, 3H), 2.58-2.66 (m, 1H), 3.07 (s, 3H),7.01-7.10 (m, 2H), 7.20-7.25 (m, 1H), 7.32-7.43 (m, 2H), 7.57-7.63 (m,2H), 10.10 (s, 1H), 11.14 (s, 1H).

Example 4-53

MS ESI m/e: 532 (M+H), 530 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.64-0.71 (m, 2H), 0.89 (t, J=7.4 Hz, 3H),0.92-0.99 (m, 2H), 1.24 (s, 3H), 1.54-1.65 (m, 2H), 2.04 (s, 3H), 2.57(t, J=7.5 Hz, 2H), 2.60-2.67 (m, 1H), 3.02 (s, 3H), 7.01-7.12 (m, 3H),7.18-7.24 (m, 1H), 7.33-7.39 (m, 1H), 7.58-7.62 (m, 2H), 10.10 (s, 1H),11.24 (s, 1H).

Example 4-54

MS ESI m/e: 653 (M+H), 651 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.60-0.71 (m, 2H), 0.90-1.01 (m, 2H), 1.27(s, 3H), 2.58-2.67 (m, 1H), 3.08 (s, 3H), 6.89-7.01 (m, 2H), 7.09-7.23(m, 4H), 7.30-7.39 (m, 1H), 7.51-7.59 (m, 1H), 7.73-7.83 (m, 1H), 9.69(brs, 1H), 11.09 (brs, 1H).

Example 4-55

MS ESI m/e: 637 (M+H), 635 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69 (m, 2H), 0.96 (m, 2H), 1.17 (s, 3H),2.62 (m, 1H), 3.09 (s, 3H), 3.26 (s, 3H), 6.95 (t, J=8.6 Hz, 1H), 7.56(d, J=8.7 Hz, 1H), 7.70-7.85 (m, 3H), 7.90-8.00 (m, 2H), 11.04 (s, 1H).

Example 4-56

MS ESI m/e: 504 (M+H), 502 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.65-0.71 (m, 2H), 0.92-0.99 (m, 2H), 1.24(s, 3H), 2.04 (s, 3H), 2.32 (s, 3H), 2.58-2.67 (m, 1H), 3.02 (s, 3H),7.00-7.10 (m, 3H), 7.20 (d, J=12.0 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H),7.56-7.63 (m, 2H), 10.10 (s, 1H), 11.24 (s, 1H).

Example 4-57

MS ESI m/e: 558 (M+H), 556 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.64-0.71 (m, 2H), 0.90-0.99 (m, 2H), 1.24(s, 3H), 1.46-1.57 (m, 2H), 1.58-1.69 (m, 2H), 1.71-1.83 (m, 2H),1.97-2.07 (m, 2H), 2.04 (s, 3H), 2.58-2.68 (m, 1H), 2.93-3.06 (m, 1H),3.03 (s, 3H), 7.00-7.14 (m, 3H), 7.24 (dd, J=1.2, 12.0 Hz, 1H), 7.36 (t,J=8.2 Hz, 1H), 7.57-7.63 (m, 1H), 10.10 (s, 1H), 11.22 (s, 1H).

Example 4-58

MS ESI m/e: 651 (M+H), 649 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.65-0.71 (m, 2H), 0.93-1.00 (m, 2H), 1.10(t, J=7.3 Hz, 3H), 1.17 (s, 3H), 2.56-2.66 (m, 1H), 3.09 (s, 3H),3.29-3.40 (m, 2H), 6.95 (t, J=8.7 Hz, 1H), 7.52-7.58 (m, 1H), 7.73-7.82(m, 3H), 7.88-7.95 (m, 2H), 11.04 (s, 1H).

Example 4-59

MS ESI m/e: 721 (M+H), 719 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.61-0.71 (m, 2H), 0.91-1.01 (m, 2H), 1.26(s, 3H), 1.35-1.60 (m, 6H), 2.59-2.67 (m, 1H), 2.99-3.12 (m, 4H), 3.07(s, 3H), 6.89-6.94 (m, 1H), 7.04-7.06 (m, 1H), 7.13-7.17 (m, 2H),7.34-7.39 (m, 1H), 7.54-7.57 (m, 1H), 7.77-7.80 (m, 1H), 10.06 (brs,1H), 11.06 (brs, 1H).

Example 4-60

MS ESI m/e: 630 (M+H), 628 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.72 (m, 2H), 0.91-1.01 (m, 2H), 1.09(t, J=7.5 Hz, 3H), 1.27 (s, 3H), 2.34 (q, J=7.0 Hz, 2H), 2.59-2.70 (m,1H), 3.09 (s, 3H), 6.91-7.08 (m, 2H), 7.34-7.40 (m, 1H), 7.56-7.69 (m,3H), 7.78-7.82 (m, 1H), 10.03 (brs, 1H), 11.09 (brs, 1H).

Example 4-61

MS ESI m/e: 533 (M+H), 531 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.73 (m, 2H), 0.91-1.01 (m, 2H), 1.22(s, 3H), 2.04 (s, 3H), 2.58-2.68 (m, 1H), 2.92 (s, 6H), 2.98 (s, 3H),6.55 (dd, J=3.0, 9.1 Hz, 1H), 6.62 (dd, J=2.6, 14.3 Hz, 1H), 6.99-7.11(m, 2H), 7.35 (t, J=7.9 Hz, 1H), 7.55-7.62 (m, 2H), 10.09 (brs, 1H),11.27 (brs, 1H).

Example 4-62

MS ESI m/e: 673 (M+H), 671 (M−H)

¹H-NMR (DMSO-d₆, 300 MHz) 0.63-0.69 (m, 2H), 0.91-0.98 (m, 2H), 1.33 (s,3H), 2.03 (s, 6H), 3.08 (s, 3H), 6.91 (dd, J=10.5, 9.6 Hz, 1H), 7.28 (s,2H), 7.55 (d, J=9.6 Hz, 1H), 7.78 (d, J=10.5 Hz, 1H), 10.09 (s, 1H),7.92 (s, 1H), 11.09 (s, 1H)

Example 4-63

MS ESI m/e: 646.0 (M+H), 644.0 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.69 (m, 2H), 0.91-0.98 (m, 2H), 1.28(s, 3H), 2.08 (s, 3H), 2.57-2.65 (m, 1H), 3.07 (s, 3H), 3.89 (s, 3H),6.91 (dd, J=12.0, 9.0 Hz, 1H), 7.07 (s, 2H), 7.55 (d, J=9.0 Hz, 1H),7.79 (d, J=12.0 Hz, 1H), 7.95 (s, 1H), 9.27 (s, 1H), 11.12 (s, 1H)

Example 4-64

MS ESI m/e: 685.9, 687.9, 684.0, 685.9

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.70 (m, 2H), 0.92-0.99 (m, 2H), 1.31(s, 3H), 2.57-2.63 (m, 1H), 3.08 (s, 6H), 6.94 (dd, J=9.0, 12.0 Hz, 1H),7.22-7.22 (m, 1H), 7.27-7.27 (m, 2H), 7.56 (d, J=9.0 Hz, 1H), 7.79 (d,J=12.0 Hz, 1H), 10.16 (s, 1H), 11.04 (s, 1H)

Example 4-65

MS ESI m/e: 571.1 (M+H),569.2 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.69 (m, 2H), 0.93-1.00 (m, 2H), 1.35(s, 3H), 2.04 (s, 6H), 2.59-2.67 (m, 1H), 3.11 (s, 3H), 4.32 (s, 1H),7.09 (dd, J=9.0, 12.0 Hz, 1H), 7.30 (s, 2H), 7.33 (d, J=9.0 Hz, 1H),7.53 (d, J=12.0 Hz, 1H), 7.94 (s, 1H), 10.11 (s, 2H), 11.12 (s, 1H)

Example 4-66

MS ESI m/e: 616.0 (M+H),614.0 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.68 (m, 2H), 0.92-0.99 (m, 2H), 1.23(s, 3H), 2.07 (s, 3H), 2.58-2.66 (m, 1H), 3.07 (s, 3H), 6.92 (dd, J=9.0,9.0 Hz, 1H), 7.28 (d, J=9.0 Hz, 2H), 7.55 (d, J=9.0 Hz, 1H), 7.64 (d,J=9.0 Hz, 2H), 7.79 (d, J=9.0 Hz, 1H), 10.10 (s, 1H), 11.06 (s, 1H)

Example 4-67

MS ESI m/e: 530 (M+H), 528 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.76 (m, 4H), 0.90-1.03 (m, 4H), 1.24(s, 3H), 1.88-2.02 (m, 1H), 2.04 (s, 3H), 2.58-2.68 (m, 1H), 3.01 (s,3H), 6.92-7.11 (m, 4H), 7.35 (t, J=8.6 Hz, 1H), 7.55-7.64 (m, 2H), 10.09(s, 1H), 11.23 (s, 1H).

Example 4-68

MS ESI m/e: 660 (M+H), 658 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.56-0.64 (m, 2H), 0.85-0.95 (m, 2H), 1.26(s, 3H), 2.04 (s, 3H), 2.46-2.60 (m, 1H), 3.20 (brs, 3H), 3.46-3.55 (m,2H), 4.01-4.11 (m, 2H), 6.91 (t, J=8.5 Hz, 1H), 6.97-7.07 (m, 1H), 7.35(t, J=7.8 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.54-7.67 (m, 2H), 7.73 (d,J=9.9 Hz, 1H), 10.09 (s, 1H), 10.13 (s, 1H).

Example 4-69

MS ESI m/e: 696 (M+H), 694 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.56-0.66 (m, 2H), 0.81-0.97 (m, 2H), 1.26(s, 3H), 2.50-2.59 (m, 1H), 3.00 (s, 3H), 3.19 (s, 3H), 3.50 (t, J=5.3Hz, 2H), 4.05 (t, J=5.1 Hz, 2H), 6.90 (t, J=8.9 Hz, 1H), 7.07-7.15 (m,1H), 7.18-7.27 (m, 2H), 7.35-7.50 (m, 2H), 7.69-7.78 (m, 1H), 9.90 (brs,1H), 10.16 (brs, 1H).

Example 4-70

MS ESI m/e: 652.0 (M+H),650.0 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.60-0.64 (m, 2H), 0.89-0.94 (m, 2H), 1.19(s, 3H), 2.55-2.62 (m, 1H), 2.99 (s, 3H), 3.03 (s, 3H), 6.88 (dd, J=8.0,8.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 7.51 (d,J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 9.91 (s, 1H), 11.02 (s, 1H)

Example 4-71

MS ESI m/e: 514.1 (M+H), 512.2 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.69 (m, 2H), 0.91-0.99 (m, 2H), 1.24(s, 3H), 2.07 (s, 3H), 2.59-2.66 (m, 1H), 3.10 (s, 3H), 4.30 (s, 1H),7.09 (dd, J=8.7, 8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.7 Hz,1H), 7.52 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 10.10 (s, 1H),11.08 (s, 1H)

Example 4-72

MS ESI m/e: 559 (M+H), 557 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.72 (m, 2H), 0.90-1.01 (m, 2H), 1.18(s, 3H), 2.57-2.67 (m, 1H), 3.07 (s, 3H), 6.93 (t, J=8.5 Hz, 1H),7.34-7.50 (m, 5H), 7.52-7.58 (m, 1H), 7.79 (dd, J=1.5, 10.2 Hz, 1H),11.06 (brs, 1H).

Example 4-73

MS ESI m/e: 668 (M+H), 666 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.72 (m, 2H), 0.92-1.01 (m, 2H), 1.30(s, 3H), 2.60-2.69 (m, 1H), 3.10 (s, 3H), 6.91-6.99 (m, 1H), 7.06-7.11(m, 1H), 7.38-7.42 (m, 1H), 7.52-7.60 (m, 1H), 7.75-7.95 (m, 5H), 9.98(brs, 1H), 11.09 (brs, 1H), 12.68 (brs, 1H).

MS ESI m/e: 681 (M+H), 679 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.72 (m, 2H), 0.90-1.02 (m, 2H), 1.31(s, 3H), 2.60-2.69 (m, 1H), 3.09 (s, 3H), 3.89 (s, 3H), 6.09-6.11 (m,1H), 6.90-6.97 (m, 1H), 7.01-7.11 (m, 3H), 7.37-7.42 (m, 1H), 7.52-7.60(m, 1H), 7.73-7.84 (m, 3H), 9.90 (brs, 1H), 11.10 (brs, 1H).

Example 4-74

MS ESI m/e: 647 (M+H), 645 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.69 (m, 2H), 0.92-0.99 (m, 2H), 1.27(s, 3H), 2.58-2.66 (m, 1H), 3.08 (s, 3H), 3.62 (s, 3H), 6.92 (t, J=−8.6Hz, 1H), 6.99-7.02 (m, 1H), 7.33 (t, J=8.1 Hz, 1H), 7.54-7.57 (m, 1H),7.61-7.66 (m, 2H), 7.79 (dd, J=1.8, 10.2 Hz, 1H), 9.05 (s, 1H), 9.58 (s,1H), 11.08 (s, 1H).

Example 4-75

MS ESI m/e: 518.0 (M+H), 516.0 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.70 (m, 2H), 0.92-1.00 (m, 2H), 1.19(t, J=7.8 Hz, 3H), 1.23 (s, 3H), 2.07 (s, 3H), 2.57-2.65 (m, 1H), 2.63(q, J=7.8 Hz, 2H), 3.02 (s, 3H), 7.07-7.09 (m, 2H), 7.21-7.25 (m, 1H),7.28 (d, J=9.0 Hz, 2H), 7.63 (d, J=8.7 Hz, 2H), 10.10 (s, 1H), 11.22 (s,1H)

Example 4-76

MS ESI m/e: 550.1 (M+H), 548.1 (M−H)

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.69 (m, 2H), 0.91-0.99 (m, 2H), 1.24(s, 3H), 2.07 (s, 3H), 2.59-2.66 (m, 1H), 3.10 (s, 3H), 4.30 (s, 1H),7.09 (dd, J=8.7, 8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.7 Hz,1H), 7.52 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 10.10 (s, 1H),11.08 (s, 1H)

Example 4-77

MS ESI m/e: 666.0 (M+H), 664.0 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.69 (m, 2H), 0.92-0.99 (m, 2H), 1.21(t, J=7.4 Hz, 3H), 1.23 (s, 3H), 2.58-2.65 (m, 1H), 3.14 (q, J=7.4 Hz,2H), 6.92 (dd, J=7.5, 10.5 Hz, 1H), 7.26 (d, J=9.0 Hz, 2H), 7.32 (d,J=9.0 Hz, 2H), 7.55 (d, J=7.5 Hz, 1H), 7.79 (d, J=10.5 Hz, 1H), 9.98 (s,1H), 11.06 (s, 1H)

Example 4-78

MS ESI m/e: 554.2 (M+H), 552.1 (M−H)

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.70 (m, 2H), 0.92-0.99 (m, 2H), 1.19(t, J=7.5 Hz, 3H), 1.22 (s, 3H), 2.55-2.63 (m, 1H), 2.63 (q, J=7.5 Hz,2H), 3.02 (s, 3H), 3.04 (s, 3H), 7.07-7.09 (m, 2H), 7.21-7.25 (m, 1H),7.25 (d, J=9.3 Hz, 2H), 7.34 (d, J=9.3 Hz, 2H), 9.95 (s, 1H), 11.22 (s,1H)

Example 4-79

MS ESI m/e: 664 (M+H), 662 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.28-0.34 (m, 2H), 0.69-0.77 (m, 2H), 1.06(brs, 3H), 2.30-2.37 (m, 1H), 2.99 (s, 3H), 4.21 (t, J=9.2 Hz, 2H), 4.72(t, J=8.6 Hz, 2H), 6.50-6.57 (m, 1H), 7.06-7.11 (m, 1H), 7.14-7.24 (m,3H), 7.29-7.35 (m, 1H), 7.35-7.41 (m, 1H), 9.91 (brs, 1H).

Example 4-80

MS ESI m/e: 661 (M+H), 659 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.65-0.69 (m, 2H), 0.93-0.98 (m, 2H), 1.27(s, 3H), 2.60-2.65 (m, 1H), 3.05 (s, 3H), 3.08 (s, 3H), 3.67 (s, 3H),6.92 (t, J=8.5 Hz, 1H), 7.00-7.03 (m, 1H), 7.34 (t, J=7.9 Hz, 1H),7.54-7.57 (m, 1H), 7.61-7.67 (m, 2H), 7.77-7.81 (m, 1H), 9.24 (s, 1H),11.08 (s, 1H).

Example 4-81

MS ESI m/e: 617 (M+H), 615 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.70 (m, 2H), 0.92-0.98 (m, 2H), 1.28(s, 3H), 2.59-2.66 (m, 1H), 3.08 (s, 3H), 5.89 (s, 2H), 6.87-6.94 (m,2H), 7.28 (t, J=7.9 Hz, 1H), 7.35-7.45 (m, 2H), 7.53-7.56 (m, 1H),7.75-7.81 (m, 1H), 8.71 (s, 1H), 11.09 (s, 1H).

Example 4-82

MS ESI m/e: 632 (M+H), 630 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.69 (m, 2H), 0.92-0.98 (m, 2H), 1.25(s, 3H), 2.60-2.64 (m, 1H), 3.08 (s, 3H), 3.99 (d, J=6.0 Hz, 2H), 5.64(t, J=6.0 Hz, 1H), 6.92 (t, J=8.5 Hz, 1H), 7.05-7.08 (m, 1H), 7.37 (t,J=7.9 Hz, 1H), 7.53-7.56 (m, 1H), 7.71-7.81 (m, 3H), 9.83 (s, 1H), 11.07(s, 1H).

Example 4-83

MS ESI m/e: 511, 513 (M+H), 509, 511 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.20 (s, 3H), 3.08 (s, 3H), 3.22 (s, 3H),3.50 (t, J=6.2 Hz, 2H), 4.04 (t, J=6.2 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H),7.35-7.51 (m, 5H), 7.55 (d, J=8.7 Hz, 2H), 11.06 (s, 1H).

Example 4-84

MS ESI m/e: 511, 513 (M+H), 509, 511 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.22 (s, 3H), 3.08 (s, 3H), 4.50 (s, 2H),7.08 (d, J=8.7 Hz, 2H), 7.38-7.52 (m, 5H), 7.55 (d, J=8.7 Hz, 2H), 10.89(s, 1H).

Example 4-85

MS ESI m/e: 497, 499 (M+H), 495, 497 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.20 (s, 3H), 3.08 (s, 3H), 3.53 (q, J=6.3Hz, 2H), 3.94 (t, J=6.4 Hz, 2H), 4.77 (t, J=5.8 Hz, 1H), 7.06 (d, J=9.0Hz, 2H), 7.37-7.51 (m, 5H), 7.55 (d, J=9.0 Hz, 2H), 11.10 (s, 1H).

Example 4-86

MS ESI m/e: 524, 526 (M+H), 522, 524 (M−H).

¹H-NMR (DMSO-d, 300 MHz) δ 1.20 (s, 3H), 2.16 (s, 6H), 2.42 (t, J=6.8Hz, 2H), 3.08 (s, 3H), 3.94 (t, J=7.2 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H),7.37-7.51 (m, 5H), 7.56 (d, J=8.7 Hz, 2H), 11.07 (s, 1H).

Example 4-87

MS ESI m/e: 681 (M+H), 679 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.72 (m, 2H), 0.90-1.02 (m, 2H), 1.31(s, 3H), 2.60-2.69 (m, 1H), 3.09 (s, 3H), 3.89 (s, 3H), 6.09-6.11 (m,1H), 6.90-6.97 (m, 1H), 7.01-7.11 (m, 3H), 7.37-7.42 (m, 1H), 7.52-7.60(m, 1H), 7.73-7.84 (m, 3H), 9.90 (brs, 1H), 11.10 (brs, 1H).

Example 4-88

MS ESI m/e: 614 (M+H), 612 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.72 (m, 2H), 0.91-1.01 (m, 2H), 1.31(s, 3H), 2.55-2.68 (m, 1H), 3.09 (s, 3H), 3.57 (s, 2H), 6.87-6.96 (m,3H), 7.25-7.28 (m, 1H), 7.55-7.58 (m, 1H), 7.78-7.81 (m, 1H), 10.49(brs, 1H), 11.08 (brs, 1H).

Example 4-89

MS ESI m/e: 668 (M+H), 666 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.71 (m, 2H), 0.91-1.01 (m, 2H), 1.29(s, 3H), 2.60-2.70 (m, 1H), 3.08 (s, 3H), 6.93 (dd, J=9.0, 9.0 Hz, 1H),7.08 (d, J=9.0 Hz, 1H), 7.40 (dd, J=9.0, 9.0 Hz, 1H), 7.56 (d, J=9.0 Hz,1H), 7.70 (s, 1H), 7.80 (d, J=9.0 Hz, 2H), 8.05 (s, 1H), 8.38 (s, 1H),9.96 (brs, 1H), 11.08 (brs, 1H), 13.27 (brs, 1H).

Example 4-90

MS EST m/e: 603 (M+H), 601 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.71 (m, 2H), 0.93-1.00 (m, 2H), 1.19(s, 3H), 2.58-2.66 (m, 1H), 3.08 (s, 3H), 6.95 (t, J=8.5 Hz, 1H),7.46-7.58 (m, 3H), 7.79 (dd, J=1.5, 10.2 Hz, 1H), 8.01 (d, J=8.7 Hz,2H), 11.01 (s, 1H), 13.14 (br, 1H).

Example 4-91

MS ESI m/e: 602 (M+H), 600 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.71 (m, 2H), 0.92-1.00 (m, 2H), 1.19(s, 3H), 2.59-2.65 (m, 1H), 3.08 (s, 3H), 6.94 (t, J=8.7 Hz, 1H),7.42-7.49 (m, 3H), 7.53-7.58 (m, 1H), 7.76-7.81 (m, 1H), 7.94 (d, J=8.7Hz, 2H), 8.07 (brs, 1H), 11.02 (s, 1H).

Example 4-92

MS ESI m/e: 616 (M+H), 614 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.70 (m, 2H), 0.92-1.00 (m, 2H), 1.18(s, 3H), 2.58-2.66 (m, 1H), 2.81 (d, J=4.5 Hz, 3H), 3.08 (s, 3H), 6.94(t, J=8.7 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.52-7.58 (m, 1H), 7.76-7.82(m, 1H), 7.90 (d, J=8.6 Hz, 2H), 8.51-8.56 (m, 1H), 11.02 (brs, 1H).

Example 4-93

MS ESI m/e: 630 (M+H), 628 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.70 (m, 2H), 0.92-1.00 (m, 2H), 1.22(s, 3H), 2.59-2.66 (m, 1H), 2.93 (brs, 3H), 3.00 (brs, 3H), 3.08 (s,3H), 6.94 (t, J=8.5 Hz, 1H), 7.42-7.49 (m, 4H), 7.53-7.57 (m, 1H),7.77-7.81 (m, 1H), 11.04 (s, 1H).

Example 4-94

MS ESI m/e: 617 (M+H), 615 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.69 (m, 2H), 0.92-0.99 (m, 2H), 1.19(s, 3H), 2.58-2.65 (m, 1H), 3.07 (s, 3H), 3.63 (s, 2H), 6.92 (t, J=8.7Hz, 1H), 7.28-7.36 (m, 4H), 7.53-7.57 (m, 1H), 7.75-7.81 (m, 1H), 11.07(br, 1H), 12.39 (br, 1H).

Example 4-95

MS ESI m/e: 661 (M+H), 659 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.61-0.71 (m, 2H), 0.90-1.00 (m, 2H), 1.28(s, 3H), 2.55-2.68 (m, 1H), 3.08 (s, 3H), 3.14 (q, J=5.6 Hz, 2H), 3.43(q, J=5.6 Hz, 2H), 4.74 (t, J=5.6 Hz, 1H), 6.20 (t, J=5.6 Hz, 1H),6.83-6.97 (m, 2H), 7.22-7.38 (m, 2H), 7.48 (s, 1H), 7.54 (d, J=9.0 Hz,1H), 7.78 (d, J=10.5 Hz, 1H), 8.75 (s, 1H), 11.08 (s, 1H).

Example 4-96

MS ESI m/e: 784 (M+H), 782 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.71 (m, 2H), 0.90-1.02 (m, 2H), 1.24(s, 3H), 2.57-2.69 (m, 1H), 3.00 (q, J=6.7 Hz, 4H), 3.07 (s, 3H), 3.35(q, J=6.7 Hz, 2H), 3.89 (t, J=6.7 Hz, 2H), 4.60 (t, J=5.7 Hz, 1H),6.86-7.05 (m, 3H), 7.10-7.21 (m, 2H), 7.35 (t, J=7.8 Hz, 1H), 7.55 (d,J=7.8 Hz, 1H), 7.71 (t, J=5.7 Hz, 1H), 7.79 (dd, J=1.8, 9.6 Hz, 1H),9.88 (s, 1H), 11.09 (s, 1H).

Example 4-97

MS ESI m/e: 530 (M+H), 528 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.71 (m, 2H), 0.91-1.00 (m, 2H), 1.25(s, 3H), 2.04 (s, 3H), 2.10 (s, 3H), 2.58-2.68 (m, 1H), 3.07 (s, 3H),5.16 (s, 1H), 5.52 (s, 1H), 7.04 (d, J=6.9 Hz, 1H), 7.11 (t, J=8.6 Hz,1H), 7.32-7.40 (m, 2H), 7.51 (dd, J=1.8, 12.6 Hz, 1H), 7.56-7.63 (m,2H), 10.10 (s, 1H), 11.22 (s, 1H).

Example 4-98

MS ESI m/e: 532 (M+H), 530 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.60-0.73 (m, 2H), 0.89-1.00 (m, 2H), 1.20(d, J=6.4 Hz, 6H), 1.24 (s, 3H), 2.04 (s, 3H), 2.56-2.68 (m, 1H),2.84-2.97 (m, 1H), 3.03 (s, 3H), 6.97-7.16 (m, 3H), 7.19-7.29 (m, 1H),7.35 (t, J=8.0 Hz, 1H), 7.53-7.66 (m, 2H), 10.10 (s, 1H), 11.22 (s, 1H).

Example 4-99

MS ESI m/e: 634.0 (M+H), 632.1 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.69 (m, 2H), 0.91-0.98 (m, 2H), 1.28(s, 3H), 2.09 (s, 3H), 2.57-2.66 (m, 1H), 3.07 (s, 3H), 6.92 (dd, J=9.0,8.7 Hz, 1H), 7.14-7.19 (m, 1H), 7.33 (dd, J=8.7, 10.5 Hz, 1H), 7.55 (d,J=8.7 Hz, 1H), 7.79 (d, J=12.0 Hz, 1H), 7.88-7.92 (m, 1H), 9.87 (s, 1H),11.09 (s, 1H)

Example 4-100

MS ESI m/e: 646 (M+H), 644 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.52-0.62 (m, 2H), 0.82-0.96 (m, 2H), 1.28(s, 3H), 2.04 (s, 3H), 2.44-2.59 (m, 1H), 3.58-3.65 (m, 2H), 4.01-4.08(m, 2H), 5.58 (t, J=4.5 Hz, 1H), 6.91 (t, J=8.6 Hz, 1H), 6.99-7.08 (m,1H), 7.30-7.45 (m, 2H), 7.57-7.65 (m, 2H), 7.66-7.75 (m, 1H), 10.09(brs, 1H), 10.12 (brs, 1H).

Example 4-101

MS ESI m/e: 670.0 (M+H), 668.0 (M−H)

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.60-0.67 (m, 2H), 0.89-0.96 (m, 2H), 1.35(s, 3H), 2.56-2.62 (m, 1H), 2.60 (s, 3H), 3.09 (s, 3H), 6.49-6.56 (m,1H), 6.84-6.99 (m, 3H), 7.22 (dd, J=2.4, 7.5 Hz, 1H), 7.46-7.52 (m, 1H)

Example 4-102

MS ESI m/e: 532.1 (M+H), 530.2 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.65-0.69 (m, 2H), 0.92-0.94 (m, 2H), 1.29(s, 3H), 2.09 (s, 3H), 2.59-2.63 (m, 1H), 3.10 (s, 3H), 4.29 (s, 1H),7.06-7.54 (m, 5H), 7.90 (d, 1H, J=6.6 Hz), 9.86 (s, 1H), 11.11 (s, 1H).

Example 4-103

MS ESI m/e: 615.1 (M+H), 613.1 (M−H)

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.71 (m, 2H), 0.91-0.98 (m, 2H), 1.23(s, 3H), 2.57-2.65 (m, 1H), 3.07 (s, 3H), 6.88-6.96 (m, 4H), 7.55 (d,J=8.7 Hz, 1H), 7.78 (d, J=10.5 Hz, 1H), 10.76 (s, 1H), 10.79 (s, 1H),11.10 (s, 1H)

Example 4-104

MS ESI m/e: 638 (M+H), 636 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.70 (m, 2H), 0.93-0.99 (m, 2H), 1.19(s, 3H), 2.57-2.65 (m, 1H), 3.08 (s, 3H), 6.90-6.98 (m, 1H), 7.48 (s,2H), 7.52-7.61 (m, 3H), 7.75-7.82 (m, 1H), 7.89 (d, J=8.6 Hz, 2H), 11.00(s, 1H).

Example 4-105

MS ESI m/e: 536 (M+H), 534 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.71 (m, 2H), 0.91-1.00 (m, 2H), 1.24(s, 3H), 2.04 (s, 3H), 2.51 (s, 3H), 2.59-2.65 (m, 1H), 3.04 (s, 3H),7.00-7.14 (m, 3H), 7.27-7.40 (m, 2H), 7.56-7.62 (m, 2H), 10.09 (brs,1H), 11.22 (brs, 1H).

Example 4-106

MS ESI m/e: 572 (M+H), 570 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.72 (m, 2H), 0.91-1.01 (m, 2H), 1.24(s, 3H), 2.51 (s, 3H), 2.60-2.67 (m, 1H), 3.01 (s, 3H), 3.04 (s, 3H),7.05-7.15 (m, 3H), 7.20-7.34 (m, 3H), 7.40 (t, J=4. Hz, 1H), 9.88 (s,1H), 11.22 (s, 1H).

Example 4-107

MS ESI m/e: 599 (M+H), 597 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.66-0.72 (m, 2H), 0.93-0.98 (m, 2H), 1.12(d, J=3.0 Hz, 3H), 2.60-2.67 (m, 1H), 3.08 (s, 3H), 6.90-6.97 (m, 1H),7.15-7.25 (m, 1H), 7.54-7.57 (m, 2H), 7.64-7.69 (m, 1H), 7.77-7.81 (m,1H), 8.31 (d, J=3.8 Hz, 1H), 11.12 (d, J=3.4 Hz, 1H), 12.60 (d, J=14.3Hz, 1H).

Example 4-108

MS ESI m/e: 657 (M+H), 655 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.74 (m, 2H), 0.90-1.01 (m, 2H), 1.26(s, 3H), 2.58-2.70 (m, 1H), 3.08 (s, 3H), 4.06 (s, 2H), 6.92 (t, J=8.6Hz, 1H), 7.36-7.47 (m, 3H), 7.51-7.60 (m, 2H), 7.78 (dd, J=1.8, 10.2 Hz,1H), 8.31 (s, 1H), 11.04 (s, 1H).

Example 4-109

MS ESI m/e: 657 (M+H), 655 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.71 (m, 2H), 0.90-0.99 (m, 2H), 1.26(s, 3H), 2.56-2.67 (m, 1H), 3.08 (s, 3H), 4.44 (s, 2H), 6.93 (t, J=8.7Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.50-7.58 (m,2H), 7.71-7.82 (m, 2H), 11.10 (s, 1H), 11.23 (s, 1H).

Example 4-110

MS ESI m/e: 643 (M+H), 641 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.72 (m, 2H), 0.90-1.00 (m, 2H), 1.27(s, 3H), 2.58-2.67 (m, 1H), 3.08 (s, 3H), 3.60-3.86 (m, 2H), 4.16-4.32(m, 2H), 6.84-6.97 (m, 2H), 7.28 (t, J=7.8 Hz, 1H), 7.40-7.73 (m, 2H),7.55 (d, J=8.4 Hz, 1H), 7.78 (dd, J=1.5, 10.2 Hz, 1H), 9.15-9.51 (brs,1H), 11.09 (s, 1H).

Example 4-111

MS ESI m/e: 613 (M+H), 611 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.65-0.74 (m, 2H), 0.91-1.01 (m, 2H), 1.11(s, 3H), 2.58-2.69 (m, 1H), 3.08 (s, 3H), 3.89 (s, 3H), 6.94 (t, J=8.4Hz, 1H), 7.26-7.34 (m, 1H), 7.51-7.58 (m, 1H), 7.59-7.67 (m, 2H),7.74-7.84 (m, 1H), 8.27 (s, 1H), 11.10 (brs, 1H).

Example 4-112

MS ESI m/e: 613 (M+H), 611 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.74 (m, 2H), 0.91-1.02 (m, 2H), 1.13(s, 3H), 2.57-2.69 (m, 1H), 3.08 (s, 3H), 4.09 (s, 3H), 6.94 (t, J=8.5Hz, 1H), 7.39-7.47 (m, 1H), 7.51-7.60 (m, 1H), 7.66-7.74 (m, 2H),7.75-7.83 (m, 1H), 8.09 (s, 1H), 11.10 (brs, 1H).

Example 4-113

MS ESI m/e: 602 (M+H), 600 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz, 120° C.) δ 0.72 (m, 2H), 0.95 (m, 2H), 1.30(s, 3H), 2.67 (m, 1H), 3.12 (s, 3H), 6.88 (t, J=8.4 Hz, 1H), 7.07 (dd,J=1.8, 8.8 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.40-7.55 (m, 3H), 7.67 (dd,J=1.8, 10.3 Hz, 1H), 8.39 (brs, 1H), 9.84 (brs, 1H), 10.90 (s, 1H).

Example 4-114

MS ESI m/e: 679 (M+H), 677 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.62-0.72 (m, 2H), 0.91-1.01 (m, 2H), 1.25(s, 3H), 2.59-2.66 (m, 1H), 3.08 (s, 3H), 3.48-3.56 (m, 2H), 3.84 (t,J=6.4 Hz, 2H), 6.92 (t, J=8.6 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.16-7.26(m, 2H), 7.44 (t, J=8.2 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.74-7.83 (m,2H), 11.10 (s, 1H).

Example 4-115

MS ESI m/e: 599 (M+H), 597 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.65-0.73 (m, 2H), 0.91-1.00 (m, 2H), 1.14(s, 3H), 2.59-2.67 (m, 1H), 3.09 (s, 3H), 6.92 (t, J=4.1 Hz, 1H),7.11-7.16 (m, 1H), 7.53-7.59 (m, 2H), 7.76-7.83 (m, 2H), 8.14 (s, 1H),11.10 (s, 1H), 13.20 (s, 1H).

Example 4-116

MS ESI m/e: 685.9 (M+H), 684.0 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.70 (m, 2H), 0.92-0.98 (m, 2H), 1.26(s, 3H), 2.57-2.65 (m, 1H), 3.08 (s, 3H), 3.09 (s, 3H), 6.94 (dd, J=9.0,8.7 Hz, 1H), 7.38 (dd, J=2.3, 8.6 Hz, 1H), 7.51-7.57 (m, 3H), 7.63 (d,J=2.3 Hz, 1H), 7.78 (dd, J=1.5, 10.2 Hz, 1H), 9.59 (s, 1H), 11.01 (s,1H)

Example 4-117

MS ESI m/e: 666.0 (M+H), 664.1 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.61-0.68 (m, 2H), 0.90-0.97 (m, 2H), 1.23(s, 3H), 2.30 (s, 3H), 2.55-2.63 (m, 1H), 3.09 (s, 3H), 6.88-6.95 (m,1H), 7.15-7.34 (m, 3H), 7.47-7.57 (m, 2H), 7.70-7.80 (m, 2H).

Example 4-118

MS ESI m/e: 630 (M+H), 628 (M−H).

¹H-NMR (CDCl3, 300 MHz) δ 0.75-0.81 (m, 2H), 1.09-1.15 (m, 2H), 1.47 (s,3H), 2.70-2.77 (m, 1H), 3.20 (s, 3H), 4.66 (s, 2H), 6.70 (t, J=8.5 Hz,1H), 6.81-6.88 (m, 2H), 7.00 (d, J=8.3 Hz, 1H), 7.43-7.55 (m, 2H), 8.12(s, 1H), 11.31 (s, 1H).

Example 4-119

MS ESI m/e: 612 (M+H), 610 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.21 (s, 3H), 3.09 (s, 3H), 3.21 (s, 3H),6.96 (t, J=8.5 Hz, 1H), 7.48 (s, 2H), 7.53-7.64 (m, 3H), 7.76-7.81 (m,1H), 7.90 (d, J=8.3 Hz, 2H), 11.13 (s, 1H).

Example 4-120

MS ESI m/e: 573 (M+H), 571 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.66-0.69 (m, 2H), 0.94-0.98 (m, 2H), 1.26(s, 3H), 2.50 (s, 3H), 2.61-2.66 (m, 1H), 3.04 (s, 3H), 6.98 (d, J=7.3Hz, 1H), 7.10-7.19 (m, 6H), 7.31-7.33 (m, 2H), 9.66 (s, 1H), 11.23 (s,1H).

Example 4-121

MS ESI m/e: 600 (M+H), 598 (M−H).

¹H-NMR (CDCl3, 300 MHz) δ 0.80-0.90 (m, 2H), 1.11-1.20 (m, 2H), 1.27 (s,3H), 2.74-2.83 (m, 1H), 3.24 (s, 3H), 6.75 (t, J=8.3 Hz, 1H), 7.37 (dd,J=1.9, 8.7 Hz, 1H), 7.45-7.57 (m, 2H), 7.80 (brs, 3H), 11.37 (s, 1H).

Example 4-122

MS ESI m/e: 671 (M+H), 669 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.60-0.67 (m, 2H), 0.87-0.95 (m, 2H), 1.21(s, 13H), 2.24 (brs, 3H), 2.54-2.61 (m, 1H), 2.69 (brs, 2H), 3.04 (s,3H), 3.07 (brs, 2H), 3.62 (brs, 2H), 6.89 (t, J=8.7 Hz, 1H), 7.24-7.29(m, 1H), 7.30-7.35 (m, 2H), 7.40-7.46 (m, 1H), 7.48-7.53 (m, 1H),7.72-7.77 (m, 1H), 11.01 (s, 1H).

Example 4-123

MS ESI m/e: 628 (M+H), 626 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.61-0.71 (m, 2H), 0.90-1.00 (m, 2H), 1.30(s, 3H), 2.50 (t, J=7.5 Hz, 2H), 2.55-2.67 (m, 1H), 2.95 (t, J=7.5 Hz,2H), 3.09 (s, 3H), 6.87-6.95 (m, 3H), 7.24 (d, J=9.0 Hz, 1H), 7.57 (d,J=9.0 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H), 10.11 (brs, 1H), 11.07 (brs, 1H).

Example 4-124

MS ESI m/e: 643 (M+H), 641 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.72 (m, 2H), 0.90-1.00 (m, 2H), 1.27(s, 3H), 2.58-2.67 (m, 1H), 3.08 (s, 3H), 3.41 (t, J=8.3 Hz, 2H), 3.85(t, J=8.3 Hz, 2H), 6.92 (t, J=8.5 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 7.05(s, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.67-7.71 (m, 1H), 7.79 (dd, J=1.8, 10.5 Hz, 1H), 11.11 (s,1H).

Example 4-125

MS EST m/e: 644 (M+H), 642 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.72 (m, 2H), 0.89-1.01 (m, 2H), 1.25(s, 3H), 2.56-2.68 (m, 1H), 3.08 (s, 3H), 4.07 (t, J=8.4 Hz, 2H), 4.45(t, J=8.4 Hz, 2H), 6.92 (t, J=8.3 Hz, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.46(t, J=8.1 Hz, 1H), 7.51-7.60 (m, 2H), 7.65-7.69 (m, 1H), 7.78 (d, J=9.3Hz, 1H), 11.10 (s, 1H).

Example 4-126

MS ESI m/e: 616 (M+H), 614 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.73 (m, 2H), 0.90-1.00 (m, 2H), 1.24(s, 3H), 2.57-2.67 (m, 1H), 3.08 (s, 3H), 6.93 (t, J=8.6 Hz, 1H), 7.08(dd, J=2.4, 8.7 Hz, 1H), 7.18 (d, J=2.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H),7.55 (d, J=8.7 Hz, 1H), 7.79 (dd, J=1.5, 10.5 Hz, 1H), 11.08 (s, 1H),11.80 (s, 1H).

Example 4-127

MS ESI m/e: 638 (M+H), 636 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.72 (m, 2H), 0.90-1.01 (m, 2H), 1.19(s, 3H), 2.57-2.66 (m, 1H), 3.09 (s, 3H), 6.94 (t, J=8.7 Hz, 1H), 7.51(brs, 2H), 7.53-7.58 (m, 1H), 7.61-7.70 (m, 2H), 7.76-7.88 (m, 3H),11.05 (brs, 1H).

Example 4-128

MS ESI m/e: 642 (M+H), 640 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.59-0.72 (m, 2H), 0.88-1.01 (m, 2H), 1.27(s, 3H), 1.29 (s, 6H), 2.55-2.67 (m, 1H), 3.07 (s, 3H), 6.86-6.97 (m,2H), 7.34 (d, J=7.9 Hz, 1H), 7.55 (dd, J=1.1, 7.9 Hz, 1H), 7.78 (dd,J=1.1, 10.6 Hz, 1H), 10.44 (brs, 1H), 11.07 (s, 18H).

Example 4-129

MS ESI m/e: 574 (M+H), 572 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.59-0.69 (m, 2H), 0.89-0.99 (m, 2H), 1.35(s, 3H), 2.52-2.66 (m, 1H), 3.07 (s, 3H), 5.25 (brs, 2H), 6.46 (d, J=6.0Hz, 1H), 6.53 (s, 1H), 6.55 (d, J=9.0 Hz, 1H), 6.90 (dd, J=9.0, 9.0 Hz,1H), 7.06 (dd, J=9.0, 9.0 Hz, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.78 (d,J=9.0 Hz, 1H), 11.06 (brs, 1H).

Example 4-130

MS ESI m/e: 640 (M+H), 638 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.60-0.71 (m, 2H), 0.89-1.00 (m, 2H), 1.29(s, 3H), 1.47-1.55 (m, 2H), 1.58-1.68 (m, 2H), 2.55-2.68 (m, 1H), 3.07(s, 3H), 6.87-6.96 (m, 3H), 7.02 (d, J=7.9 Hz, 1H), 7.52-7.58 (m, 1H),7.78 (dd, J=1.9, 10.2 Hz, 1H), 10.66 (brs, 1H), 11.07 (brs, 1H).

Example 4-131

MS ESI m/e: 472 (M+H), 470 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.59-0.70 (m, 2H), 0.89-1.01 (m, 2H), 1.36(s, 3H), 2.56-2.67 (m, 1H), 3.10 (s, 3H), 4.28 (s, 1H), 5.24 (s, 2H),6.42-6.62 (m, 3H), 6.99-7.14 (m, 2H), 7.26-7.36 (m, 1H), 7.46-7.57 (m,1H), 11.08 (s, 1H).

Example 4-132

MS ESI m/e: 716 (M+H), 714 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.74 (m, 2H), 0.91-1.04 (m, 2H), 1.28(s, 3H), 1.36 (s, 9H), 2.48 (s, 3H), 2.59-2.69 (m, 1H), 3.08 (s, 3H),6.94 (t, J=8.6 Hz, 1H), 7.17-7.24 (m, 2H), 7.38-7.57 (m, 3H), 7.79 (d,J=10.3 Hz, 1H), 11.0 (brs, 1H).

Example 4-133

MS EST m/e: 694 (M+H), 692 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.62-0.71 (m, 2H), 0.92-1.01 (m, 2H), 1.17(s, 3H), 1.95 (s, 3H), 2.59-2.69 (m, 1H), 3.08 (s, 3H), 3.54 (s, 3H),6.94 (d, J=9.0 Hz, 1H), 7.52-7.60 (m, 5H), 7.79 (d, J=10.4 Hz, 1H), 11.0(brs, 1H).

Example 4-134

MS ESI m/e: 620 (M+H), 618 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.27 (s, 3H), 2.06 (s, 3H), 3.10 (s, 3H),3.49-3.60 (m, 2H), 3.89-4.01 (m, 2H), 4.78 (brs, 1H), 6.95 (t, J=8.7 Hz,1H), 7.03-7.10 (m, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.51-7.60 (m, 2H), 7.68(s, 1H), 7.78-7.82 (m, 1H), 10.1 (brs, 1H), 11.3 (brs, 1H).

Example 4-135

MS ESI m/e: 634 (M+H), 632 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.27 (s, 3H), 2.65-2.79 (m, 2H), 2.06 (s,3H), 3.09 (s, 3H), 3.39-3.50 (m, 2H), 3.82-3.94 (m, 2H), 4.46 (brs, 1H),6.95 (t, J=8.7 Hz, 1H), 7.07-7.10 (m, 1H), 7.38 (t, J=8.0 Hz, 1H),7.55-7.58 (m, 2H), 7.68 (s, 1H), 7.78-7.81 (m, 1H), 10.1 (brs, 1H), 11.3(brs, 1H).

Example 4-136

MS ESI m/e: 650 (M+H), 648 (M-1).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.27 (s, 3H), 2.05 (s, 3H), 3.09 (s, 3H),3.70-3.90 (m, 2H), 4.02 (q, J=7.8 Hz 1H), 4.55 (t, J=5.7 Hz, 1H), 4.77(d, J=5.4 Hz, 1H), 6.94 (t, J=8.7 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 7.37(t, J=8.1 Hz, 1H), 7.56 (d, J=8.7 Hz, 2H), 7.68 (s, 1H), 7.79 (dd,J=1.5, 10.2 Hz, 1H), 10.10 (s, 1H), 11.30 (s, 1H).

Example 4-137

MS ESI m/e: 650 (M+H), 648 (M-1).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.27 (s, 3H), 2.05 (s, 3H), 3.09 (s, 3H),3.70-3.90 (m, 2H), 4.02 (q, J=7.1 Hz, 1H), 4.55 (brs, 1H), 4.77 (d,J=3.9 Hz, 1H), 6.94 (t, J=8.5 Hz, 1H), 7.04 (d, J=8.7 Hz, 1H), 7.37 (t,J=8.1 Hz, 1H), 7.56 (d, J=8.7 Hz, 2H), 7.68 (s, 1H), 7.79 (dd, J=2.4,10.8 Hz, 1H), 0.1.10 (s, 1H), 11.30 (s, 1H).

Example 4-138

MS ESI m/e: 723 (M+H), 721 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.65-0.72 (m, 2H), 0.91-1.01 (m, 2H), 1.27(s, 3H), 1.91 (s, 3H), 2.59-2.69 (m, 1H), 2.93 (s, 6H), 3.10 (s, 3H),6.98 (t, J=8.6 Hz, 1H), 7.43-7.60 (m, 5H), 7.80 (d, J=10.3 Hz, 1H), 11.0(brs, 1H).

Example 4-139

MS ESI m/e: 630 (M+H), 628 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.63-0.71 (m, 2H), 0.92-1.00 (m, 2H), 1.26(s, 3H), 1.82 (brs, 3H), 2.58-2.67 (m, 1H), 3.08 (s, 3H), 3.16 (brs,3H), 6.94 (t, J=8.7 Hz, 1H), 7.30-7.46 (m, 3H), 7.47-7.60 (m, 2H),7.76-7.82 (m, 1H), 11.02 (s, 1H).

Example 4-140

MS ESI m/e: 658 (M+H), 656 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 0.61-0.72 (m, 2H), 0.92-1.01 (m, 2H), 1.28(s, 3H), 2.20 (s, 6H), 2.58-2.66 (m, 1H), 3.08 (s, 3H), 6.94 (t, J=8.6Hz, 1H), 7.29-7.35 (m, 1H), 7.36-7.40 (m, 1H), 7.42-7.48 (m, 1H),7.51-7.58 (m, 2H), 7.75-7.82 (m, 1H), 11.00 (s, 1H).

Example 4-141

MS ESI m/e: 633 (M+H), 631 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.27 (s, 3H), 1.81-1.93 (m, 2H), 2.05 (s,3H), 2.75-2.87 (m, 2H), 3.09 (s, 3H), 3.91 (t, 2H, J=6.2 Hz), 6.93 (t,1H, J=8.5 Hz), 7.04-7.10 (m, 1H), 7.38 (t, 1H, J=8.1 Hz), 7.48-7.59 (m,2H), 7.69-7.86 (m, 5H), 10.18 (s, 1H), 11.21 (s, 1H).

Example 4-142

MS ESI m/e: 664 (M+H), 662 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.26 (s, 3H), 1.46-1.57 (m, 1H), 1.65-1.80(m, 1H), 2.05 (s, 3H), 3.08 (s, 3H), 3.15-3.36 (m, 2H), 3.40-3.51 (m,1H), 3.78-3.91 (m, 1H), 3.98-4.11 (m, 1H), 4.46-4.56 (m, 2H), 6.94 (t,1H, J=8.7 Hz), 7.04-7.10 (m, 1H), 7.37 (t, 1H, J=8.1 Hz), 7.52-7.59 (m,2H), 7.65-7.69 (m, 1H), 7.79 (dd, 1H, J=1.9, 10.5 Hz), 10.10 (s, 1H),11.28 (s, 1H).

Example 4-143

MS ESI m/e: 664 (M+H), 662 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.26 (s, 3H), 1.43-1.59 (m, 1H), 1.67-1.79(m, 1H), 2.04 (s, 3H), 3.08 (s, 3H), 3.15-3.32 (m, 2H), 3.40-3.50 (m,1H), 3.78-3.91 (m, 1H), 3.97-4.10 (m, 1H), 4.45-4.54 (m, 2H), 6.94 (t,1H, J=8.7 Hz), 7.04-7.09 (m, 1H), 7.37 (t, 1H, J=8.1 Hz), 7.53-7.59 (m,2H), 7.65-7.69 (m, 1H), 7.79 (dd, 1H, J=1.9, 10.2 Hz), 10.10 (s, 1H),11.27 (s, 1H).

Example 4-144

MS ESI m/e: 648 (M+H), 646 (M−H).

¹H-NMR (CDCL3, 300 MHz) δ 1.42 (s, 3H), 1.53-1.82 (m, 4H), 2.17 (s, 3H),3.21 (s, 3H), 3.68 (t, 2H, J=6.2 Hz), 3.96-4.04 (m, 2H), 6.70 (t, 1H,J=8.3 Hz), 7.05-7.12 (m, 1H), 7.22-7.56 (m, 6H), 7.70 (s, 1H), 11.47 (s,1H).

Example 4-145

MS ESI m/e: 670 (M+H), 668 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.26 (s, 3H), 1.66-1.75 (m, 2H), 3.02 (s,3H), 3.08 (s, 3H), 3.42 (q, 2H, J=5.9 Hz), 3.88-3.91 (m, 2H), 4.45 (t,1H, J=5.1 Hz), 6.94 (t, 1H, J=8.6 Hz), 7.12-7.15 (m, 1H), 7.23-7.29 (m,2H), 7.42 (t, 1H, J=7.9 Hz), 7.54-7.57 (m, 1H), 7.78 (dd, 1H, J=10.5,1.7 Hz), 9.92 (s, 1H), 11.26 (s, 1H).

Example 4-146

MS ESI m/e: 634 (M+H), 632 (M−H).

¹H-NMR (DMSO-d₆, 400 MHz) δ 1.25 (s, 3H), 1.66-1.75 (m, 2H), 3.08 (s,3H), 3.42 (q, 2H, J=4.5 Hz), 3.86-3.93 (m, 2H), 4.46 (t, 1H, J=3.8 Hz),6.95 (t, 1H, J=6.4 Hz), 7.11 (dd, 1H, J=1.7, 6.4 Hz), 7.22 (d, 1H, J=1.6Hz), 7.35 (d, 1H, J=6.4 Hz), 7.53-7.58 (m, 1H), 7.79 (dd, 1H, J=1.4, 7.8Hz), 11.27 (s, 1H), 11.84 (s, 1H).

Example 4-147

MS ESI m/e: 577 (M+H), 575 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.19 (s, 3H), 1.65-1.76 (m, 2H), 3.08 (s,3H), 3.43 (q, 2H, J=5.9 Hz), 3.86-3.94 (m, 2H), 4.46 (t, 1H, J=5.3 Hz),6.95 (t, 1H, J=8.7 Hz), 7.38-7.51 (m, 5H), 7.52-7.58 (m, 1H), 7.79 (dd,1H, J=1.9, 10.2 Hz), 11.25 (s, 1H).

Example 4-148

MS ESI m/e: 650 (M+H), 648 (M−H).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.26 (s, 3H), 1.70-1.72 (m, 2H), 3.08 (s,3H), 3.42 (q, 2H, J=5.7 Hz), 3.89-3.91 (m, 2H), 3.99 (d, 2H, J=5.9 Hz),4.44 (t, 1H, J=5.3 Hz), 5.64 (t, 1H, J=6.1 Hz), 6.94 (t, 1H, J=8.6 Hz),7.11 (d, 1H, J=7.0 Hz), 7.39 (t, 1H, J=8.3 Hz), 7.55 (d, 1H, J=8.1 Hz),7.70-7.81 (m, 3H), 9.83 (s, 1H), 11.25 (s, 1H).

INDUSTRIAL APPLICABILITY

The compound of the present invention shows superior p15 proteininducing action and/or p27 protein inducing action and/or MEK inhibitoryaction.

In addition, the compound of the present invention shows superiorantitumor activity, and anti-rheumatism activity.

Therefore, the compound can be a pharmaceutical agent effective for theprophylaxis or treatment of a disease caused by undesirable cellproliferation, particularly, tumor or rheumatism.

This application is based on patent application Nos. 174770/2004 and327111/2004 filed in Japan, the contents of which are herebyincorporated by reference.

1.-24. (canceled)
 25. A method of preparing a compound of the formula:

comprising (a) reacting

with cyclopropylamine to form

(b) reacting the product of step (a) with

to form

(c) converting the product of step (b) to

(d) converting the product of step (c) to

(e) reacting the product of step (d) with

to form

(f) reacting the product of step (e) with

to form

and (g) reacting the product of step (f) with

to form


26. A compound of the formula:

or a salt or solvate thereof.
 27. A compound of the formula:

or a salt or solvate thereof.
 28. A compound of the formula:

or a salt or solvate thereof.
 29. A compound of the formula:

or a salt or solvate thereof.
 30. A compound of the formula:

or a salt or solvate thereof.
 31. A compound of the formula:

or a salt or solvate thereof.